Note: Descriptions are shown in the official language in which they were submitted.
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INHIBITORS OF PAI-1 FOR TREATMENT OF MUSCULAR CONDITIONS
CROSS REFERENCE TO RELATED APPLICATION
[00011 This application claims the benefits of U.S. Provisional Application
No.
60/777,521, filed February 27, 2006, which is incorporated herein by reference
in its entirety.
FIELD
100021 This invention describes novel methods of treating muscle damage,
muscle
wasting, muscle degeneration, muscle atrophy or reduced rates of muscle repair
associated with
various conditions such as muscular dystrophy, through the use of small-
molecule PAI-1
inhibitors.
BACKGROUND
[0003] There are currently few treatments for deleterious condition of the
muscle,
including, for example, muscle damage, muscle wasting, muscle degeneration,
muscle atrophy or
reduced rates of muscle repair. Such deleterious conditions of the muscle can
result from normal
conditions of use or trauma, or quite frequently, through chronic disease
states. One such
chronic disease state with very serious implications and of particular
relevance to this invention
is muscular dystrophy, a severe genetic disease associated with muscle wasting
that has separate
and diverse forms. Duchenne muscular dystrophy (DMD) results from mutations in
the
dystrophin protein, which ultimately leads to severe skeletal muscle wasting
and death in early
adulthood. Cardiomyopathy is also observed in DMD. The precise mechanisms for
the
progression of the disease are unknown, however, and treatment modalities have
not been
1
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adequately developed. The outlook for any given muscular dystrophy sufferer is
correlated with
the degree of the severity of their disease. Some may live a normal lifespan
and suffer from
moderate symptoms while those afflicted with more severe forms of the disease
can face a
considerably bleaker outlook. Typical treatment modalities include
rehabilitative exercises,
physical therapy and the like. Corrective orthopedic surgery is employed in
some instances and
glucocorticoids may be used to prevent muscle wasting in D1VID, but chronic
administration of
such agents are associated with a plethora of well-documented side effects.
Clearly there is a
current and urgent need for new treatments for this debilitating disease. This
invention addresses
this and other important ends.
SUMMARY OF THE INVENTION
[0004] This invention provides, inter alia, methods of treating muscle damage,
muscle
wasting, muscle degeneration, muscle atrophy or reduced rate of muscle repair
comprising
administering an effective amount of a compound of a PAI-inhibitor, as
provided herein, to a
mammal in need thereof
[0005] The invention also provides, inter alia, pharmaceutical compositions
useful for
treating muscle damage, muscle wasting, muscle degeneration, muscle atrophy or
reduced rate of
muscle repair comprising a PAI-inhibitor, as provided herein, and a
pharmaceutically acceptable
excipient.
[0006] The invention also provides, inter alia, uses of compounds and
pharmaceutical
compositions of the present invention in the manufacture of a medicament for
treating muscle
damage, muscle wasting, muscle degeneration, muscle atrophy or reduced rate of
muscle repair.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0007] The present invention provides, inter alia, methods of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair
comprising administering a PAI-1 inhibitor to a mammal in need thereof.
[0008] In some embodiments, the PAI-1 inhibitors useful for the methods of
this
invention have a molecular weight of less than 1,000.
[0009] In some aspects, the PAI-1 inhibitors useful in the methods of this
invention are
described in US20060014725, US20050215626, US20050119327, US20050119326,
US20050119296, US20050113439, US20050113438, US20050113438, US20050113436,
US20050113428, US20050096377, US20050070592, US20050070587, US20050070585,
US20050070584, US20040266733, US20040138283, US20040122070, US20040116504,
2
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US20040116488, US20030125371, US20030045560, US20030032626, US20030018067, and
US20030013732, which are herein incorporated by reference in their entirety
and for all
purposes.
[0010] In some aspects, this invention describes a method of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair, wherein
said method comprises the administration of an effective amount of a compound
of formula (I),
or a pharmaceutically acceptable salt, solvate or ester thereof, to a manunal
in need thereof:
OH
R3 O~X
Rd N R2
RI (~)
wherein:
X is a chemical bond, -CH2- or -C(O)- ;
Ri is Ct-Ca alkyl, (-CH2).-C3-C6 cycloalkyl, wherein n is an integer of from 0
to 3,
pyridinyl, -CH2-pyridinyl, phenyl or benzyl, the rings of the cycloalkyl,
pyridinyl, phenyl and
benzyl groups being optionally substituted by, from I to 3 groups selected
from halogen, CI-C4
alkyl, CI -C3 perfluoroalkyl, -O-CI -C3 perfluoroalkyl, CI -C3 alkoxy, -OH, -
NH2, or -NO2;
R2 is H, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, CI-C3
perfluoroalkyl,
-CH2OH or CH2OAc;
R3 is H, halogen, Ci-C6 alkyl, CI-C3 perfluoroalkyl, CI-C6 alkoxy, C3-C6
cycloalkyl,
-CH2-C3-C6 cycloalkyl, C3-C6 cycloalkenyl, -CH2-C3-C6 cycloalkenyl, -NH2, or -
NO2;
Rd 1S C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, C3-C6 cycloalkenyl, -CH2-C3-C6
cycloalkenyl, phenyl, benzyl, pyridinyl, or -CH2-pyridinyl, with the rings of
these groups being
optionally substituted by from I to 3 groups selected from halogen, CI -C4
alkyl, Ci-C3
perfluoroalkyl, -O-C1-C3 perfluoroalkyl, CI-C3 alkoxy, -OH, -NH2, -NOZ or
(CO)CI-C6 alkyl.
[0011] Compounds of formula (I) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formulas
(II), (III) and (IV):
3
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0
0
R3 HO 0 HO O
R4 r\ ~ ~ R3
N R2 =; ~ ~ R2
R R1 (II) , R 1 (III)
0
HO O
R4 R3
~ ~ ~
R2
N
(N)
wherein:
R,, R2, R3, and R4 are as defined previously for formula (I).
[00121 Exemplary compounds of formulas I, II, III, and IV include those in
which:
Ri is CI-C8 alkyl, (-CH2)n C3-C6 cycloalkyl, wherein n is an integer of from 0
to 3,
pyridinyl, -CH2-pyridinyl, phenyl or benzyl, the rings of the cycloalkyl,
pyridinyl, phenyl and
benzyl groups being optionally substituted by, from 1 to 3 groups selected
from halogen, Ct-C4
alkyl, CI-C3 perfluoroalkyl, -O-Cl-C3 perfluoroalkyl, Ci-C3 alkoxy, -OH, -NH2,
or -N02;
R2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, CI-C3
perfluoroalkyl,
-CH2OH or CH2OAc;
R3 is H, halogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, Ci-C6 alkoxy, C3-C6
cycloalkyl,
-CH2-C3-C6 cycloalkyl, C4-C6 cycloalkenyl, -CH2-C4-C6 cycloalkenyl, -NH2, or -
N02; and
R4 is phenyl substituted by from I to 3 groups selected from halogen, CI-C4
alkyl, Ci-C3
perfluoroalkyl, -O-Cl-C3 perfluoroalkyl, C1-C3 alkoxy, -OH, -NH2, -NO2 or
(CO)CI-C6 alkyl; or
a pharmaceutically acceptable salt, solvate, or ester form thereof. In certain
embodiments, R4 is
at the 4, 5, or 6 position.
100131 Exemplary compounds of formulas I, II, III, and IV include those in
which:
Ri is Ci-C8 alkyl, (-CHZ)n C3-C6 cycloalkyl, wherein n is an integer of from 0
to 3, or
benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being
optionally
substituted by, from 1 to 3 groups selected from, halogen, Ci-C4 alkyl, Ci-C3
perfluoroalkyl, -0-
C,-C3 perfluoroalkyl, or CI-C3 alkoxy;
R2 is H, -CHZOH or CH2OAc;
R3 is H;
4
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R4 is phenyl optionally substituted by from I to 3 groups selected from
halogen, C1-C3
alkyl, Ci-C3 perfluoroalkyl, -O-Ci-C3 perfluoroalkyl Ci-C3 alkoxy or (CO)Ci-C6
alkyl; or a
pharmaceutically acceptable salt, solvate, or ester form thereof. In certain
embodiments, R4 is
phenyl substituted by from 1 to 3 groups selected from halogen, CI-C3 alkyl,
CI-C3
perfluoroalkyl, -0-Ci-C3 perfluoroalkyl Ci-C3 alkoxy or (CO)Ci-C6 alkyl.
100141 Exemplary compounds of formulas I, II, III, and IV iriclude those in
which:
Ri is benzyl, the benzyl group being optionally substituted by from 1 to 3
groups selected
from halogen, Ci-C4 alkyl, C1-C3 perfluoroalkyl, -O-Cl-C3 perfluoroalkyl, or
Cl-C3 alkoxy;
R2 is H;
R3 is H; and
R4 is phenyl optionally substituted by from 1 to 3 groups selected from
halogen, Cj-C3
alkyl, CI -C3 perfluoroalkyl, -0-Ci-C3 perfluoroalkyl CI -C3 alkoxy or (CO)Ci-
C6 alkyl; or a
pharmaceutically acceptable salt, solvate, or ester form thereof. In certain
embodiments, R4 is
phenyl substituted by from I to 3 groups selected from halogen, Cj-C3 alkyl,
Cj-C3
perfluoroalkyl, -O-Ci-C3 perfluoroalkyl CI-C3 alkoxy or (CO)Ci-C6 alkyl.
[0015] Compounds of formula (I) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formula
(V) or formula (VI):
O
R5 O
R3 HO O Rs R HO O
3
\N R ~ .r
R
R$ H Rz
z R7
or N
1
R6 Ri
R7
(V) (VI)
wherein:
Ri is Ci-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or benzyl, the
rings of the
cycloalkyl and benzyl groups being optionally substituted by from 1 to 3
groups selected from
halogen, Ct-C4 alkyl, Ci-C3 perfluoroalkyl, -O-C,-C3 perfluoroalkyl, Ci-C3
alkoxy, -OH, -NH2,
or -NOZ;
R2 is H, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or Ci-C3
perfluoroalkyl;
R3 is H, halogen, CI -C6 alkyl, CI -C3 perfluoroalkyl, CI -C6 alkoxy, C3-C6
cycloalkyl,
-CH2-C3-C6 cycloalkyl, -NH2, or -NO2; and
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R5, R6 and R7 are independently H, halogen, CI-C3 alkyl, CI-C3 perfluoroalkyl,
-0-Ci-C3
perfluoroalkyl, CI -C3 alkoxy, -OH, -NHZ, or -NO2i or a pharmaceutically
acceptable salt, solvate,
or ester form thereof.. In certain embodiments, at least one of R5, R6 and R7
is not H.
[0016] Exemplary compounds of formulas V and VI include those in which:
R, is benzyl, the benzyl group being optionally substituted by from I to 3
groups selected
from halogen, Ci-C4 alkyl, Ci-C3 perfluoroalkyl, -O-Cl-C3 perfluoroalkyl, or
Ci-C3 alkoxy;
R2 is H;
R3 is H; and
R5, R6 and R7 are independently H, halogen, CVC3 alkyl, C1-C3 perfluoroalkyl, -
O-Cl-C3
perfluoroalkyl or Ci-C3 alkoxy; or a pharmaceutically acceptable salt,
solvate, or ester form
thereof. In certain embodiments, at least one of R5, R6 and R7 is not H.
[0017] Exemplary compounds of formula I include:
{1-Methyl-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-
Methyl-6-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-Ethyl-6-[4-
(trifluoromethoxy)phenyl]-1 H-indol-3-yl } (oxo)acetic acid; { 1-Ethyl-6-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-Benzyl-6-[4-
(trifluoromethoxy)phenyl]-l H-indol-3-yl} (oxo)acetic acid; { 1-Benzyl-6-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-[4-(tert-
Butyl)benzyl]-6-[4-
(trifluoromethyl)phenyl]-1 H-indol-3-yl} (oxo)acetic acid; { 1-[4-(tert-
Butyl)benzyl]-6-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-Benzyl-5-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {6-[4-(tert-
Butyl)phenyl]-I-methyl-
1H-indol-3-yl}(oxo)acetic acid; [5-(4-Acetylphenyl)-1-benzyl-1H-indol-3-
yl](oxo)acetic
acid; { 1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1 H-indol-3-yl} (oxo)acetic
acid; { 1-Benzyl-4-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;{1-Benzyl-5-[4-(tert-
butyl)phenyl]-1H-
indol-3-yl}(oxo)acetic acid; [1-Benzyl-5-(3-chloro-4-fluorophenyl)-1H-indol-3-
yl](oxo)acetic
acid; {1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic
acid; {l-Benzyl-7-
[4-(trifluoromethoxy)phenyl]-1 H-indol-3-yl} (oxo)acetic acid; [1-Benzyl-7-(3-
chloro-4-
fluorophenyl)-1 H-indol-3-yl](oxo)acetic acid; { 1-(4-tert-Butylbenzyl)-5-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-Benzyl-4-[4-
(trifluoromethoxy)phenyl]-1 H-indol-3-yl} (oxo)acetic acid; [1-Benzyl-6-(3-
chlorophenyl)-1H-
indol-3-yl](oxo)acetic acid;{1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-IH-indol-
3-yl}(oxo)acetic
acid; {1-(4-Methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-
yl}(oxo)acetic acid;{1-(4-
Fluorobenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;
[1-Butyl-5-(4-
chlorophenyl)-1 H-indol-3-yl](oxo)acetic acid; [ 1-Butyl-5-(3-chlorophenyl)-1H-
indol-3-
6
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yl](oxo)acetic acid; [1-Butyl-5-(3-methoxyphenyl)-lH-indol-3-yl](oxo)acetic
acid; [1-Butyl-5-
(4-methoxyphenyl)-1H-indol-3-yl](oxo)acetic acid;{I-Butyl-5-[4-
(trifluoromethyl)phenyl]-1H-
indol-3-yl}(oxo)acetic acid; [1-(4-tert-Butylbenzyl)-5-(3-methylphenyl)-1H-
indol-3-
yl](oxo)acetic acid; [ 1-(4-tert-Butylbenzyl)-5-(3-methoxyphenyl)-IH-indol-3-
yl](oxo)acetic
acid; [1-(4-tert-Butylbenzyl)-5-(4-tert-butylphenyl)-IH-indol-3-yl](oxo)acetic
acid; [1-(4-tert-
Butylbenzyl)-5-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid; [1-(4-tert-
Butylbenzyl)-5-(4-
chlorophenyl)-IH-indol-3-yl](oxo)acetic acid; [1-(4-tert-Butylbenzyl)-5-(2-
methylphenyl)-IH-
indol-3-yl](oxo)acetic acid; { 1-(2-Ethylbutyl)-5-[4-(trifluoromethoxy)phenyl]-
1 H-indol.-3-
yl}(oxo)acetic acid;{2-[(Acetyloxy)methyl]-1-(4-methylbenzyl)-5-[4-
(trifluoromethoxy)phenyl]-
I H-indol-3 -yl } (oxo)acetic acid; {2-(Hydroxymethyl)-1-(4-methylbenzyl)-5-[4-
(trifluoromethoxy)phenyl]-IH-indol-3-yl}(oxo)acetic acid; {2-
[(Acetyloxy)methyl]-I-benzyl-5-
[4-(trifluoromethoxy)phenyl]-IH-indol-3-yl}(oxo)acetic acid; {1-Benzyl-2-
(hydroxymethyl)-5-
[4-(trifluoromethoxy)phenyl]-IH-indol-3-yl}(oxo)acetic acid; [5-(3-
Chlorophenyl)-1-
cyclopenty]-1 H-indol-3-yl]-oxo-acetic acid; [5-(3-chlorophenyl)-1-
(cyclobutylmethyl)-1H-indol-
3-yl](oxo)acetic acid; [5-(3-chlorophenyl)-1-(3-methylcyclopropyl)-IH-indol-3-
yl](oxo)acetic
acid; [5-(3-chlorophenyl)-I-(cyclohexylmethyl.)-IH-indol-3-yl](oxo)acetic
acid; [5-(4-
trifluoromethylphenyl)-1-(cyclopentyl)-1H-indol-3-yl](oxo)acetic acid; [5-(4-
trifluoromethylphenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid; [5-
(4-
trifluoromethylphenyl)-1-(3-methylcyclopentyl)-IH-indol-3-yl](oxo)acetic acid;
[5-(4-
trifluoromethylphenyl)-1-(cyclohexylmethyl)-1 H-indol-3-yl](oxo)acetic acid;
[5-(4-
trifluoromethylphenyl)-1-(cyclopentylpropyl)- I H-indol-3-yl](oxo)acetic acid;
[5-(3-
trifluoromethylphenyl)-1-(cyclopentyl)-1H-indol-3-yl](oxo)acetic acid; [5-(3-
trifluoromethylphenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid;[5-
(3-
trifluoromethylphenyl)-1-(3-methylcyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
[5-(3-
trifluoromethylphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid; [5-
(3-
trifluoromethylphenyl)-I-(cyclopentylpropyl)-IH-indol-3-yl](oxo)acetic acid;
or[5-(4
methoxyphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid; or a
pharmaceutically
acceptable salt, solvate or ester form thereof.
[00181 Methods of synthesizing compounds of formula I are provided in US
Patent No.
7,074,817, incorporated herein by reference in its entirety and for all
purposes, and are thus not
described herein.
[0019} In some aspects, this invention describes a method of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair, wherein
said method comprises the administration of an effective amount of a compound
of formula
7
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(VII), or a pharmaceutically acceptable salt, solvate or ester thereof, to a
mammal in need
thereof:
0 R5
R3
('~
Ra~ ~ Ri
N
H
R2O
(VII)
wherein:
Ri is hydrogen, C2-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or Ct-C3
perfluoroalkyl, wherein the alkyl and cycloalkyl groups are optionally
substituted with halogen,
-CN, C1-C6 alkoxy, -OH, -NH2, or -NO2;
R2 is hydrogen, CI-C$ alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, thienyl,
CH2-
thienyl, furanyl, CHZ-furanyl, oxazoyl, CH2-oxazoyl, phenyl, benzyl, CH2-
naphthyl, wherein the
alkyl group and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl,
phenyl, benzyl, and napthyl
groups are optionally substituted by from 1 to 3 groups selected from halogen,
CI -C3 alkyl, Ci -
C3 perfluoroalkyl, -O-C1-C3 perfluoroalkyl, -S-Ct-C3 perfluoroalkyl, CI-C3
alkoxy, -OCHF2,
-CN, -COOH, -CH2CO2H, -C(O)CH3, -C02R6, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -
NO2;
R3 is hydrogen, halogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, C1-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyl, -NH2, or -NO2;
R4 is C3-C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, -CH2-C3-C6
cycloalkyl,
thienyl, furanyl, oxazoyl, phenyl, benzo[b]furan-2-yl, benzo[b]thien-2-yl,
benzo[1,3]dioxol-5-yl,
naphthyl, wherein the alkyl groups and the rings of the cycloalkyl, thienyl,
furanyl, oxazoyl,
phenyl, benzofuranyl, benzothienyl, and napthyl groups are optionally
substituted by from 1 to 3
groups selected from halogen, CI -C3 alkyl, Ci-C3 perfluoroalkyl, -0-Ci-C3
perfluoroalkyl, -S-Ci-
C3 perfluoroalkyl, Ct-C3 alkoxy, -OCHF2, -CN, -COOH, CH2CO2H, -C(O)CH3,
-C(O)OR6, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2;
R5 is CI-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, pyridinyl, -CH2-
pyridinyl,
thienyl, CH2-thienyl, furanyl, CHZ-furanyl, oxazoyl, CH2-oxazoyl, phenyl,
benzyl,
benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl, CH2-
naphthyl, 9H-
fluoren-l-yl, 9H-fluoren-4-yl, 9H-fluoren-9-yl, 9-fluorenone-1-yl, 9-
fluorenone-2-yl, 9-
fluorenone-4-yl, CH2-9H-fluoren-9-yl, wherein the alkyl group and the rings of
the cycloalkyl,
pyridinyl, thienyl, furanyl, oxazoyl, phenyl, benzyl, benzofuranyl,
benzothienyl, napthyl,
fluorenyl, and fluorenone groups are optionally substituted by from 1 to 3
groups selected from
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halogen, Ci-C3 alkyl, C3-C6 cycloalkyl, Ci-C3 perfluoroalkyl, -O-Ci-C3
perfluoroalkyl, -S-Cl-C3
perfluoroalkyl, C1-C3 alkoxy, phenoxy, -OCHFzi -CN, -COOH, -CH2CO2H, -C(O)CH3,
-C02R6,
-C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2, wherein the phenoxy group are
optionally
substituted by from I to 3 groups selected from halogen, CI-C3 alkyl, or Ci-C3
perfluoroalkyl;
and
R6 is C,-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or benzyl; or a
pharmaceutically acceptable salt, solvate, or ester form thereof.
100201 Exemplary compounds of formula VII include those in which Ri-R3 and Rs-
R6
are as defined herein for formula VII, and R4 is thienyl, furanyl, oxazoyl,
phenyl, benzo[b]furan-
2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxoi-5-y], or naphthyl, wherein the
rings of the thienyl,
furanyl, oxazoyl, phenyl, benzofuranyl, benzothienyl, and napthyl groups are
optionally
substituted by from I to 3 groups selected from halogen, CI -C3 alkyl, CI -C3
perfluoroalkyl, -O-
CI-C3 perfluoroalkyl, -S-Cl-C3 perfluoroalkyl, Ci-C3 alkoxy, -OCHF2, -CN, -
COOH,
-CH2CO2H, -C(O)CH3, - C(O)OR6, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2.
10021] Exemplary compounds of formula (VII) include:
[3-(4-chlorobenzoyl)-5-(4-chlorophenyl)-IH-indol-i-yl]acetic acid; [3-
(Benzo[b]thiophene-2-
carbonyl)-5-(4-methylphenyl)-IH-indol-1-yl]-acetic acid; [3-(4-chlorobenzoyl)-
5-(4-
methylphenyl)-IH-indol-1-yl]-acetic acid; or a pharmaceutically acceptable
salt, solvate, or ester
form thereof.
[0022] Methods of synthesizing compounds of formula I are provided in US
Publication No. 20040122070, incorporated herein by reference in its entirety
and for all
purposes, and are thus not described herein.
100231 In some aspects, this invention describes a method of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair, wherein
said method comprises the administration of an effective amount of a compound
of formula
(VHI), or a pharmaceutically acceptable salt, solvate or ester thereof, to a
mammal in need
thereof:
R6 R5
R3
R4~ R,
N
\ OH
R2/O (VIII)
wherein:
9
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Ri is hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or CI-C3
perfluoroalkyl, wherein the alkyl and cycloalkyl groups are optionally
substituted by halogen,
-CN, CI-C6 alkoxy, -OH, -NHZ, or -NO2;
R2 is hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, thienyl,
CH2-
thienyl, furanyl, CH2-furanyl, oxazoyl, CH2-oxazoyl, phenyl, benzyl, or CH2-
naphthyl; wherein
the alkyl group and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl,
phenyl, benzyl, and
naphthyl groups are optionally substituted by from 1 to 3 groups selected from
halogen, Ci-C3
alkyl, CI-C3 perfluoroalkyl, -O-Ci-C3 perfluoroalkyl, -S-CI-C3 perfluoroalkyl,
CI-C3 alkoxy,
-OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -C(O)OR7, -C(O)NHZ, -S(O)2CH3, -OH, -
NH2,
or -NO2;
R3 is hydrogen, halogen, CI-C6 alkyl, Ci-C3 perfluoroalkyl, Ci-C6 alkoxy, C3-
C6
cycloalkyl, or -CH2-C3-C6 cycloalkyl;
R4 is C3-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, thienyl, CH2-
thienyl, furatryl,
oxazoyl, phenyl, benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-
yl, or naphthyl;
wherein the alkyl group and the rings of the cycloalkyl, thienyl, furanyl,
oxazoyl, phenyl,
benzofuranyl, benzothienyl, and napthyl groups are optionally substituted by
from I to 3 groups
selected from halogen, Ci-C3 alkyl, Ci-C3 perfluoroalkyl, -0-CI-C3
perfluoroalkyl, -S-CI-C3
perfluoroalkyl, CI -C3 alkoxy, -OCHFZ, -C(O)CH3, -C(O)OR7, -C(O)NH2, -
S(O)2CH3, -OH,
-NH2, or -NO2;
RS is CI-C8 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, pyridinyl, -CH2-
pyridinyl,
thienyl, CH2-thienyl, furanyl, CH2-furanyl, oxazoyl, CH2-oxazoyl, phenyl,
benzyl,
benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl, CH2-
naphyl, 9H-
fluoren-l-yl, 9H-fluoren-4-yl, 9H-fluoren-9-yl, 9-fluorenone-l-yl, 9-
fluorenone-2-yl, 9-
fluorenone-4-yl, or CH2-9H-fluoren-9-yl; wherein the alkyl group and the rings
of the cycloalkyl,
pyridinyl, thienyl, furanyl, oxazoyl, phenyl, benzyl, benzofuranyl,
benzothienyl, napthyl,
fluorenyl, and fluorenone groups are optionally substituted by from 1 to 3
groups selected from
halogen, CI-C3 alkyl, C3-C6 cycloalkyl, Ci-C3 perfluoroalkyl, -O-Ci-C3
perfluoroalkyl, -S-Ci-C3
perfluoroalkyl, CI-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3i -
C(O)OR7,
-C(O)NH2, -S(O)2CH3, -OH, -NH2, -NO2, or phenoxy, the phenoxy group being
further
optionally substituted by from I to 3 groups selected from halogen, Ci-C3
alkyl, or CI-C3
perfluoroalkyl;
R6 is hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, pyridyl,
thienyl,
CH2-thienyl, furanyl, CH2-furanyl, oxazoyl, CH2-oxazoyl, phenyl, benzyl,
benzo[b]furan-2-yl,
benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, CH2-1-naphthyl, or CH2-2-naphyl;
wherein the alkyl
CA 02643731 2008-08-26
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group and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl,
benzyl, benzofuranyl,
benzothienyl, and napthyl groups are optionally substituted by from I to 3
groups selected from
halogen, Ci-C3 alkyl, CI-C3 perfluoroalkyl, -O-C1 -C3 perfluoroalkyl, -S-CI-C3
perfluoroalkyl,
Ci-C3 alkoxy, -OCHFZ, -CN, -COOH, -CH2CO2H, -C(O)CH3, -C(O)OR7, -C(O)NH2, -
S(O)2CH3,
-OH, -NH2, or -NOZ;
or R5 and R6taken together are C3-C6 cycloalkyl, 3-indan-l-yl, 1,2,3,4-
tetrahydronaphthalen-l-yl, chroman-4-yl, 4H-chromen-4-yl, thiochroman-4-yl, 9H-
fluoren-9-yl,
9,10-dihydroanthracen-9-yl, 9H-xanthen-9-yl, 9H-thioxanthen-9-yl, 6,7,8,9-
tetrahydro-5H-
benzocyclohepten-5-yl, or 10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5-yl,
wherein these
groups are optionally substituted by from 1 to 3 groups selected from halogen,
CI-C3 alkyl, Ci-
C3 perfluoroalkyl, -O-Ci-C3 perfluoroalkyl, -S-Ci-C3 perfluoroalkyl, CI-C3
alkoxy, -OCHF2,
-CN, -COOH, -CH2COZH, -C(O)CH3, -C(O)OR7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -
NO2;
and
R7 is Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or benzyl; or a
pharmaceutically acceptable salt, solvate, or.ester form thereof.
[0024] Exemplary compounds of formula VIII include those in which Ri-R3 and RS-
R7
are as defined herein for formula VIII, and
R4 is thienyl, furanyl, oxazoyl, phenyl, benzo[b]furan-2-yl, benzo[b]thien-2-
yl,
benzo[1,3]dioxol-5-yl, or naphthy; wherein the rings of the thienyl, furanyl,
oxazoyl, phenyl,
benzofuranyl, benzothienyl, and napthyl groups are optionally substituted by
from I to 3 groups
selected from halogen, CI-C3 alkyl, CI-C3 perfluoroalkyl, -O-Cl-C3
perfluoroalkyl, -S-Ci-C3
perfluoroalkyl, Ci-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2COZH, -C(O)CH3, C02R7,
-C(O)NHZ, -S(O)2CH3, -OH, -NH2, or -NO2; or a pharmaceutically acceptable
salt, solvate, or
ester form thereof.
[0025] Compounds of formula (VIII) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formula
(IX):
R8 R3 R6 R
~9'I\
~ R,
R10 N OH
R2
O
(IX)
wherein:
11
CA 02643731 2008-08-26
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Ri is hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or Ci -
C3
perfluoroalkyl, wherein the alkyl and cycloalkyl groups are optionally
substituted by halogen,
-CN, C1-C6 alkoxy, -OH, -NH2, or -NO2;
R2 is hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, or -CH2-C3-C6 cycloalkyl,
wherein the
alkyl group and the rings of the cycloalkyl groups are optionally substituted
by from I to 3
groups selected from halogen, Ci-C3 alkyl, CI -C3 perfluoroalkyl, -O-Ci-C3
perfluoroalkyl, -S-Ci -
C3 perfluoroalkyl, CI-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -
C(O)OR7,
-C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2;
R3 is hydrogen, halogen, Ci-C6 alkyl; C1-C3 perfluoroalkyl, CI-C6 alkoxy, C3-
C6
cycloalkyl, or -CH2-C3-C6 cycloalkyl;
R5 is C1-C8 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, phenyl, benzyl,
naphthyl, or
CH2-naphyl, wherein the alkyl group and the rings of the cycloalkyl, phenyl,
and benzyl groups
are optionally substituted by from I to 3 groups selected from halogen, CI-C3
alkyl, C3-C6
cycloalkyl, C1-C3 perfluoroalkyl, -0-Ci-C3 perfluoroalkyl, -S-Ci-C3
perfluoroalkyl, Ct-C3
alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -C(O)OR7, -C(O)NH2, -S(O)2CH3,
-OH,
-NH2, -NO2i or phenoxy; the phenoxy group being optionally substituted by from
1 to 3 groups
selected from halogen, CI -C3 alkyl, or C1-C3 perfluoroalkyl;
R6 is hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, or -CH2-C3-C6 cycloalkyl,
wherein the
alkyl group and the rings of the cycloalkyl groups are optionally substituted
by from I to 3
groups selected from halogen, CI-C3 alkyl, CI-C3 perfluoroalkyl, -O-CI-C3
perfluoroalkyl, -S-Q-
C3 perfluoroalkyl, CI -C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -
C(O)NH2,
-S(O)ZCH3, -OH, -NH2, or -NOZ;
or R5 and R6 taken together are a C3-C6 cycloalkyl group optionally
substituted by from I
to 3 groups selected from halogen, CI-C3 alkyl, Ci-C3 perfluoroalkyl, -O-CI-C3
perfluoroalkyl,
-S-Ci-C3 perfluoroalkyl, CI-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3,
-C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2;
R7 is CI-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or benzyl; and
R8, Rg, Rio are each independently hydrogen3 halogen, CI-C3 alkyl, Ci-C3
perfluoroalkyl,
-O-Ci-C3 perfluoroalkyl, -S-CI-C3 perfluoroalkyl, C1-C3 alkoxy, -OCHF2, -
C(O)CH3, -C(O)OR7,
-C(O)NHZ, -S(O)2CH3, -OH, -NH2, or -NOZ; or a pharmaceutically acceptable
salt, solvate, or
ester form thereof.
[0026] Compounds of formula (VIII) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formula
(X):
12
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(\ jR10 ~ R5
Ra
Ri
H
RZO
(X)
wherein:
R, is hydrogen or Ci-C6 alkyl;
R2 is hydrogen or C1-C3 alkyl, optionally substituted by halogen;
RS is C i-C8 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, phenyl, benzyl,
or thienyl,
wherein the* alkyl group and the rings of the cycloalkyl, phenyl, thienyl and
benzyl groups are
optionally substituted by from 1 to 3 groups selected from halogen, CI-C3
alkyl, C3-C6
cycloalkyl, Ci-C3 perfluoroalkyl, -0-Ci-C3 perfluoroalkyl, -S-Ci-C3
perfluoroalkyl, C,u-C3
alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -C(O)NHZ, -S(O)2CH3, -OH, -
NH2, or
-NO2i
R6 is hydrogen or CI-C6 alkyl;
R7 is C,-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or benzyl; and
Rg, R9, Rio are each independently hydrogen, halogen, CI-C3 alkyl, Ci-C3
perfluoroalkyl,
-O-CI-C3 perfluoroalkyl, -S-CI-C3 perfluoroalkyl, CI-C3 alkoxy, -OCHF2, -
C(O)CH3, -C(O)NH2,
-S(O)2CH3, -OH, -NH2, or -NO2i or a pharmaceutically acceptable salt or ester
form thereof.
[00271 Exemplary compounds of formula VIII, IX, and X include those in which
R5 is
CI -Cg alkyl, C3-C6 cycloalkyl, or -CH2-C3-C6 cycloalkyl, wherein the alkyl
group and the rings
of the cycloalkyl group are optionally substituted by from 1 to 3 groups
selected from halogen,
Ci-C3 alkyl, C3-C6 cycloalkyl, CI-C3 perfluoroallcyl, -O-Cl-C3 perfluoroalkyl,
-S-Ci-C3
perfluoroalkyl, C, -C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -
C(O)OR7,
-C(O)NH2, -S(O)ZCH3, -OH, -NH2, -NOZ, or phenoxy; the phenoxy group being
optionally
substituted by from l to 3 groups selected from halogen, CI -C3 alkyl, or Ci-
C3 perfluoroalkyl.
100281 Exemplary compounds of formula (VIII) include:
{5-(3-trifluoromethoxyphenyl)-3-[1-(4-trifluoromethylphenyl)-ethyl]-indol-l-
yl}-acetic acid;
{3-[3,5-bis(trifluoromethyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indol-l-
yl}acetic) acid;
[3-[3,5-bis(tri fluoromethyl)benzyl]-5-(2,4-dichlorophenyl)-1H-indol-1-
yl]acetic acid; {3-[3,5-
bi s(tri fluoromethyl)benzyl]-5-[3-(trifluoromethyl)phenyl]-1 H-indol-l-yl }
acetic acid; {5-(3-
chlorophenyl)-3-[1-(2-thienyl)ethyl]-1H-indol-l-yl}acetic acid; [3-(l-
phenylethyl)-5-(3-
trifluoromethyl-phenyl)-indol-l-yl]acetic acid; [3-(1-thiophen-2-yl-ethyl)-5-
(3-trifluoromethyl-
13
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phenyl)-indol-l-ylJacetic acid; [3-(1-cyclohexyl-ethyl)-5-(3-trifluoromethyl-
phenyl)-indol-l-
yl]acetic acid; [3-(4-isopropyl-benzyl)-5-(3-trifluoromethyl-phenyl)-indol-l-
yl]acetic acid; [5-
(2,4-dichloro-phenyl)-3-(1,3-dimethyl-butyl)-indol-l-yl]-acetic acid; [5-(2,4-
dichloro-phenyl)-3-
(1-phenyl-ethyl)-indol-l-yl]-acetic acid; [3-(1-cyclohexyl-ethyl)-5-(2,4-
dichloro-phenyl)-indol-
1-yl]-acetic acid; or a pharmaceutically acceptable salt, solvate, or ester
form thereof.
[00291 Methods of synthesizing compounds of formula VIII are provided in
US20060178412, incorporated herein by reference in its entirety and for all
purposes, and are
thus not described herein_
[00301 In some aspects, this invention describes a method of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair, wherein
said method comprises the administration of an effective amount of a compound
of formula (XI),
or a pharmaceutically acceptable salt, solvate or ester thereof, to a mammal
in need thereof:
0
HO O
R3 ~ ~ R2
N
~ =
Rl
(XI)
wherein:
Ri is the moiety:
R4N.
X,
Rs or
R, is Cl-Cg alkyl, benzo[1,3]dioxo-5yl-methyl, cycloalkylalkyl where the alkyl
chain is
Ci-C3, heteroarylalkyl where the alkyl chain is Cl-C3, arylalkyl where the
alkyl chain is Ci-C3,
preferably selected from benzyl, CHZ-1-naphthyl, CH2-2-naphyl, CHZCH2-phenyl,
or CH2CH2-
napthyl, wherein the alkyl, cycloalkyl, heteroaryl, and aryl groups are
optionally substituted by
from I to 3 groups selected from halogen, CI-C3 alkyl, C1-C3 haloalkyl, Cl-C3
perfluoroalkyl,
CI-C3 alkoxy, Ci-C3 perfluoroalkoxy, C1-C3 alkylthio, Ci-C3
perfluoroalkylthio, -OCHF2, -CN,
-C(O)CH3, -C02R7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NOZ;
R4 is hydrogen, halogen, Ci-C3 alkyl, C1-C3 haloalkyl, C1-C3 perfluoroalkyl,
Cj-C3
alkoxy, Ci-C3 perfluoroalkoxy, Ci-C3 alkylthio, Ci-C3 perfluoroalkylthio, -
OCHF2, -CN,
-COOH, -CH2CO2H, -C(O)CH3, -CO2R7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2;
14
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X is 0, S, or NH;
RS is Ci-Cg alkyl, CI-C3 perfluoroalkyl, C3-C6 cycloalkyl, -CH2-C3-C6
cycloalkyl,
heteroaryl, -CH2-heteroaryl, phenyl, or arylalkyl where the alkyl chain is CI -
Cg, wherein the
rings of the cycloalkyl, heteroaryl, phenyl, and aryl groups are optionally
substituted by from 1
to 5 groups selected from halogen, C1-C6 alkyl, C1-C3 haloalkyl, CI-C3
perfluoroalkyl, Ci-C3
alkoxy, CI-C3 perfluoroalkoxy, C1-C3 alkylthio, Ci-C3 perfluoroalkylthio,
heteroaryl,
-OCHF2, -CN, -COOH, -CH2CO2H, -C(O)CH3, -C02R7, -C(O)NH2, -S(O)2CH3, -OH, -
NH2, or
-NO2;
R2 is hydrogen, C1-C6 alkyl, -CH2-C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl,
wherein the
alkyl and cycloalkyl groups are optionally substituted by halogen, -CN, Cj-C6
alkoxy, -COOH,
-CH2CO2H, -C(O)CH3, -C02R7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NOZ;
R3 is hydrogen, halogen, Ci-C$ alkyl, Cl-Ca alkenyl, Cl-Cg alkynyl, C3-C6
cycloalkyl,
-CH2-C3-C6 cycloalkyl, heteroaryl, or phenyl, wherein the alkyl, alkenyl,
alkynyl, cycloalkyl,
heteroaryl, and phenyl groups are optionally substituted by from 1 to 3 groups
selected from
halogen, Ci-C3 alkyl, Ci-C3 haloalkyl, C1-C3 perfluoroalkyl, Ci-C3 alkoxy, C1-
C3
perfluoroalkoxy, Cti-C3 alkylthio, Ci-C3 perfluoroalkylthio, -OCHF2, -CN, -
COOH, -CH2CO2H,
-C(O)CH3, -C02R7, -C(O)NH2, -S(O)2CH3i -OH, -NH2, or -NO2;
or R3 is the moiety X-R6;
Rb is C,-C8 alkyl, C1-Cg alkenyl, Q-Cs alkynyl, C3-C6 cycloalkyl, -CH2-C3-C6
cycloalkyl,
heteroaryl, phenyl, aryl-alkyl where the alkyl chain is Cl-C8, CH2CH2-phenyl,
or CHzCH2-
napthyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and aryl
groups are
optionally substituted by from I to 3 groups selected from halogen, C1-C3
alkyl, CI-C3
perfluoroalkyl, -O-CI -C3 perfluoroalkyl, -S-CI -C3 perfluoroalkyl, C,-C3
alkoxy, -OCHF2, -CN, -
C(O)CH3, -C02R7, -S(0)2CH3, -OH, -NHZ, or -NO2; and
R7 is C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or Ci-Cg aryl-
alkyl;
or a pharmaceutically acceptable salt, solvate, or ester form thereof.
100311 In certain aspects R, is Ci-Cg alkyl, benzo[1,3]dioxo-5yl-methyl,
cycloalkylalkyl where the alkyl chain is CV=C3, heteroarylalkyl where the
alkyl chain is CI-C3,
benzyl, CH2-1-naphthyl, CH2-2-naphyl, CH2CH2-phenyl, or CH2CH2-napthyl,
wherein the alkyl,
cycloalkyl, heteroaryl, benzyl, phenyl, and naphthyl groups are optionally
substituted by from I
to 3 groups selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3
perfluoroalkyl, C,-C3
alkoxy, C1-C3 perfluoroalkoxy, Ci-C3 alkylthio, CI-C3 perfluoroalkylthio, -
OCHF2, -CN,
-C(O)CH3, -COZR7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NOZ.
CA 02643731 2008-08-26
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100321 Compounds of formula (XI) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formula
(XII) or (XIII):
O
HO O O
HO 0
R3 N R2 ~r O
RZ
/ N
Ra~L/- \ R,
O~
()UI) 5 (XM)
wherein:
Ri is CI -C8 alkyl, benzo[1,3]dioxo-5yl-methyl, cycloalkylalkyl where the
alkyl chain is
Ci-C3, heteroarylalkyl where the alkyl chain is Ci-C3, arylalkyl where the
alkyl chain is Ci-C3,
preferably selected from benzyl, CH2-1 -naphthyl, CH2-2-naphyl, CH2CH2-phenyl,
or CH2CH2-
napthyl, wherein the alkyl, cycloalkyl, heteroaryl and aryl groups are
optionally substituted by
from I to 3 groups selected from halogen, Ci-C3 alkyl, Ci-C3 perfluoroalkyl, -
O-Cl-C3
perfluoroalkyl, S-Ci-C3 perfluoroalkyl, Ci-C3 alkoxy,,-OCHFZ, -CN, -COOH, -
CH2CO2H, -
C(O)CH3, -C02R7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NOZ;
R4 is hydrogen, halogen, CI-C6 alkyl, Ci-C3 haloalkyl, CI-C3 perfluoroalkyl, -
O-Ci-C3
perfluoroalkyl, -S-Cl-C3 perfluoroalkyl, Ci-C3 alkoxy, -OCHF2, -CN, -C(O)CH3, -
CO2R7, -S(O)-
2CH3, -OH, -NH2, or -NO2;
R5 is CI-C8 alkyl, CI-C3 perfluoroalkyl, -CH2-C3-C6 cycloalkyl, -CH2-
heteroaryl, or aryl-
alkyl where the alkyl chain is CI -Cg, wherein the rings of the cycloalkyl,
heteroaryl, and aryl
groups are optionally substituted by from 1 to 5 groups selected from halogen,
C1-C6 alkyl, Ci-
C3 perfluoroalkyl, -O-Ci-C3 perfluoroalkyl, heteroaryl, S-C1-C3
perfluoroalkyl, Cj-C3 alkoxy,
-OCHF2i -CN, -C(O)CH3, -CO2R7, -S(O)ZCH3, -OH, -NHZ, or -NO2;
R2 is hydrogen, Ci-C6 alkyl, or CI-C3 perfluoroalkyl, wherein the alkyl group
is
optionally substituted by halogen, -CN, Cj-C6 alkoxy, -COOH, -CH2CO2H, -
C(O)CH3,
-CO2R7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NO2;
R3 is hydrogen, halogen, C1-C8 alkyl, Ci-Ca alkenyl, Ci-Ca alkynyl, C3-C6
cycloalkyl,
-CH2-C3-C6 cycloalkyl, heteroaryl, or phenyl, wherein the alkyl, alkenyl,
alkynyl, cycloalkyl,
heteroaryl, and phenyl groups are optionally substituted by from 1 to 3 groups
selected from
halogen, Ci-C3 alkyl, CI-C3 perfluoroalkyl, -0-C1-C3 perfluoroalkyl, -S-Cl-C3
perfluoroalkyl,
C,-Cs alkoxy, -OCHF2, -CN, -C(O)CH3, -C02R7, -S(O)2CH3, -OH, -NH2, or -NOZ;
16
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R6 is Ci-C8 alkyl, Ci-Cg alkenyl, CI-Cg alkynyl, C3-C6 cycloalkyl, -CH2-C3-
C6cycloalkyl,
heteroaryl, phenyl, aryl-alkyl where the alkyl chain is Ci-C8, CH2CH2-phenyl,
or CH2CH2-
napthyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and aryl
groups are
optionally substituted by from 1 to 3 groups selected from- halogen, CI-C3
alkyl, CI-C3
perfluoroalkyl, -0-Ci-C3 perfluoroalkyl, preferably -OCF3, -S-Ci-C3
perfluoroalkyl, CI-C3
alkoxy, -OCHF2, -CN, -C(O)CH3, -COZR7, -S(0)2CH3, -OH, -NH2, or -NO2; and
R7 is Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or aryl-alkyl
where the alkyl
chain is Ci-Cg; or a pharmaceutically acceptable salt, solvate, or ester form
thereof.
100331 Exemplary compounds of the formula (XI), (XII), and (XIII) include
those in
which R5 is CI -C$ alkyl, Ci-C3 perfluoroalkyl, C3-C6 cycloalkyl, -CH2-C3-C6
cycloalkyl,
heteroaryl, -CH2-heteroaryl, phenyl, or arylalkyl where the alkyl chain is Cl-
Cg, wherein the
rings of the cycloalkyl, heteroaryl, phenyl, and aryl groups are optionally
substituted by from 1
to 5 groups selected from halogen, CI-C3 alkyl, CI-C3 haloalkyl, CI-C3
perfluoroalkyl, Ci-C3
alkoxy, CI-C3 perfluoroalkoxy, Ci-C3 alkylthio, Ci-C3.perfluoroalkylthio, -
OCHF2, -CN,
-COOH, -CH2CO2H, -C(O)CH3, -C02R7, -C(O)NH2, -S(O)2CH3, -OH, -NH2, or -NOz;
100341 Exemplary compounds of formula (XI) include:
(1- {4-[(4-cyanobenzyl)oxy]phenyl} -IH-indol-3-yl)(oxo)acetic acid; { 1-[4-(3-
methoxy-
benzyloxy)-phenyl]1H-indol-3-yl}-oxo-acetic acid; {1-[4-(3-chloro-benzyloxy)-
phenyl]IH-
indol-3-yl}-oxo-acetic acid; {1-[4-(4-cyanobenzyloxy)-phenyl]-5-fluoro-lH-
indol-3-yl}-oxo-
acetic acid; {1-[4-(3,5-dimethoxy-benzyloxy)-phenyl]-5-fluoro-lH-indol-3-yl}-
oxo-acetic acid;
{ 1-[4-(3-chloro-benzyloxy)-phenyl]-5-methyl-lH-indol-3-yl}-oxo-acetic acid;
{1-[4-(2,4-
dichlorobenzyloxy)-phenyl]-5-methyl-lH-indol-3-yl} -oxo-acetic acid; {5-Chloro-
1-[3-(4-cyano-
benzyloxy)-phenyl]IH-indol-3-yl}-oxo-acetic acid; {5-Chloro-l-[3-(3,5-
dimethoxy benzyloxy)-
phenyl]1H-indol-3-yl}-oxo-acetic acid; {1-[4-(2,3,5,6-tetrafluoro-4-
trifluoromethyl-benzyloxy)-
phenyl]IH-indol-3-yl}-oxo-acetic acid; {1-[4-(2,6-dichloro-pyridin-4-
ylmethoxy)-phenyl]1H-
indol-3-yl}-oxo-acetic acid; [1-(4-{[5-(ethoxycarbonyl)-2-
furyl]methoxy}phenyl)-5-fluoro-lH-
indol-3- yl](oxo)acetic acid; {1-[4-(2,6-dichloropyridin-4-ylmethoxy)-phenyl]-
5-methyl-lH-
indol-3-yl}-oxo-acetic acid; {5-Chloro-l-[3-(2,3,5,6-tetrafluoro-4-
trifluoromethyl-benzyloxy)-
phenyl] 1H-indol-3-yl}-oxo-acetic acid; [5-chloro-l-(3- {[5-(ethoxycarbonyl)-2-
furyl]methoxy}phenyl)-1H-indol-3- yl](oxo)acetic acid; 5-Chloro-l-[3-(2,6-
dichloro-pyridin-4-
ylmethoxy)-phenyl] 1H-indol-3-yl}-oxo-acetic acid; [1,5-bis-(4-
trifluoromethoxy-phenyl)-1H-
indol-3-yl]-oxo-acetic acid; [1,5-bis-(4-trifluoromethoxy-phenyl)-IH-indol-3-
yl]-oxo-acetic
acid; { 1-(4-fluorobenzyl)-5-[2-(4-fluorophenyl)ethoxy]-]H-indol-3-yl}
(oxo)acetic acid, [ 1-
benzyl-5-(2-chloro-4-trifluoromethyl-phenoxy)-]H-indol-3-yl] (oxo)acetic acid;
(1-benzyl-5-
17
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WO 2007/098278 PCT/US2007/005069
benzyloxy-1 H-indol-3-yl)-oxo-acetic acid; (5-allyloxy-l-cyclobutylmethyl-1 H-
indol-3-yl)-oxo-
acetic acid; (5-allyloxy-l-phenethyl-lH-indol-3-yl)-oxo-acetic acid; (5-
allyloxy-l-
benzo[1,3]dioxol-5-ylmethyl-lH-indol-3-yl)-oxo-acetic acid; (5-allyloxy-l-[2-
(4-
methoxyphenyl)-ethyl]-1H-indol-3-yl)-oxo-acetic acid; (5-allyloxy-l-[2-
naphthalene-l-yl-ethyl]-
1 H-indol-3-yl)-oxo-acetic acid; (5-allyloxy-l-[2-(3-trifluoromethylphenyl)-
ethyl]-1H-indol-3-
yl)-oxo-acetic acid; (5-allyloxy-l-[2-(4-bromophenyl)-ethyl]-1H-indol-3-yl)-
oxo-acetic acid;
{ 1-[4-(4-tert-butyl-benzyloxy)-phenyl]-5-methyl-lH-indol-3-yl}-oxo-acetic
acid; {1-[4-(4-
[1,2,3]thiadiazol-4-yl-benzyloxy)-phenyl]-1H-indol-3-yl}-oxo-acetic acid; {5-
Chloro-l-[3-(4-
[1,2,3]thiadiazol-4-yl-benzyloxy)-phenyl]1H-indol-3-yl}-oxo-acetic acid; or a
pharmaceutically
acceptable salt, solvate, or ester form thereof.
[00351 Methods of synthesizing compounds of formula (XI) are provided in
US20040138283 incorporated herein by reference in its entirety and for all
purposes, and are
thus not described herein.
[00361 In some aspects, this invention describes a method of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair, wherein
said method comprises the administration of an effective amount of a compound
of formula
(XIV) or (XV), or a pharmaceutically acceptable salt, solvate or ester
thereof, to a mammal in
need thereof:
0 0 O 0
C
R21`\ O R~\\ OX
R3 N R3 ' ~
OH
R R
(XIV) (XV)
wherein:
X is hydrogen, an alkali metal or a basic amine moiety;
Ri is hydrogen, Ci-C8 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl,
pyridinyl, -CH2-
pyridinyl, phenyl or benzyl, wherein the rings of the cycloalkyl, pyridinyl,
phenyl and benzyl
groups are optionally substituted by from I to 3 groups selected from halogen,
Cj-C6 alkyl, Ci-
C6 perfluoroalkyl, -O-Cl-C6 perfluoroalkyl, Ci-C6 alkoxy, -OH, -NH2, or -NO2i
R2 is hydrogen, halogen, CI-C6 alkyl, CI-C3 perfluoroalkyl, Ci-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyl, hydroxy, -NHZ, or -NO2;
18
CA 02643731 2008-08-26
WO 2007/098278 PCT/US2007/005069
R3 is hydrogen, halogen, CI-C6 alkyl, Ci-C3 perfluoroalkyl, CI-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyl, hydroxy, -NHZ, -NOz, phenyl, benzyl,
benzyloxy, pyridinyl,
or -CH2-pyridinyl, wherein the rings of these groups are optionally
substituted by from I to 3
groups selected from phenyl, halogen, CI-C6 alkyl, Ci-C6 perfluoroalkyl, -O-Ci-
C6
perfluoroalkyl, CI -C6 alkoxy, -OH, -NHZ, or -NOZ; or a pharmaceutically
acceptable salt, solvate,
or ester form thereof.
[0037] Compounds of formula (XIV) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formula
()cVI) and (XVII):
O O O O
RZ\\ O R3 RZ\\ \ O
I
R3 / N
Ri R,
(XVI) (XVII)
wherein:
R, is hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl,
pyridinyl, -CH2-
pyridinyl, phenyl or benzyl, wherein the rings of the cycloalkyl, pyridinyl,
phenyl and benzyl
groups are optionally substituted by from I to 3 groups selected from halogen,
CI-C6 alkyl, Ct-
C6 perfluoroalkyl, -0-Ci-C6 perfluoroalkyl, Ci-C6 alkoxy, -OH,-NH2, or-NO2;
R2 is hydrogen, halogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, CI-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyi, -NH2, or -NO2;
R3 is hydrogen, halogen, CI-C6 alkyl, Ci-C3 perfluoroalkyl, C1-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyl, hydroxy, -NH2, -NO2, phenyl, benzyl,
benzyloxy, pyridinyl,
or -CH2-pyridinyl, wherein the rings of these groups are optionally
substituted by from I to 3
groups selected from halogen, Ci-C6 alkyl, CI-C6 perfluoroalkyl, -O-CI-C6
perfluoroalkyl, CI-C6
alkoxy, -OH, -NH2, or -NO2; or a pharmaceutically acceptable salt, solvate, or
ester form thereof.
[0038] Compounds of formula (XIV) include the following compounds, or
phanmaceutically acceptable salt, solvate or ester forms thereof, of formula
(XVIII) and (XIX):
19
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WO 2007/098278 PCT/US2007/005069
O p R4\ O
RZ\\ O R, RZ p
I
wX ~ \
~
\
C R,
Ri
/
s k\
R ~/
~ P6 (XVIII) (XIX)
wherein:
Ri is hydrogen, CI-C8 alkyl, preferably Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-
C6
cycloalkyl, or benzyl, wherein the rings of the cycloalkyl and benzyl groups
are optionally
substituted by from I to 3 groups selected from halogen, CI -C6 alkyl, CI -C6
perfluoroalkyl, -0-
Ci-C6 perfluoroalkyl, Ci-C6 alkoxy, -OH, -NH2, or-NO2;
R2 is hydrogen, halogen, CI-C6 alkyl, Ci-C3 perfluoroalkyl, preferably -CF3,
CI-C6
alkoxy, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, hydroxy, -NH2, or -NOZ;
R4, R5 and R6 are each independently hydrogen, phenyl, halogen, CI-C3 alkyl,
CI-C3
perfluoroalkyl, -O-CI -C3 perfluoroalkyl, CI -C3 alkoxy, -OH, -NH2, or -NOZ;
or a
pharmaceutically acceptable salt, solvate, or ester form thereof.
[0039] Exemplary compounds of the formula (XIV), (XV), (XVI), (XVII), (XVIII),
and
(XIX) include those in which R, is CI-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6
cycloalkyl,
pyridinyl, -CHZ-pyridinyl, phenyl or benzyl, wherein the rings of the
cycloalkyl, pyridinyl,
phenyl and benzyl groups are optionally substituted by from I to 3 groups
selected from halogen,
C1-C6 alkyl, Ci-C6 perfluoroalkyl, -0-Ci-C6 perfluoroalkyl, Ci-C6 alkoxy, -OH,
-NH2, or -NOZ.
[0040] Exemplary compounds formula (XV) include those wherein the alkali metal
is
for example, sodium, potassium, lithium, calcium, magnesium, or the like and
the basic amine
moiety is, for example, amonia, primary amines, secondary amines, tertiary
amines, pyridine,
aromatic amines, benzyl amines, and the like.
[0041] Exemplary compounds of formulas (XIV) and (XV) include:
9-(4-Methylbenzyl)-6-[4-(trifluoromethoxy)phenyl]-1,9-dihydropyrano[3,4-
b]indole-3,4-dione;
9-Benzyl-6-[4-(trifluoromethoxy)phenyl]-1,9-dihydropyrano[3,4-b]indole-3,4-
dione; 9-(4=
Methylbenzyl)-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-b]indole-3,3-dione; 9-
(4-tert-
butylbenzyl)-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-b] indole-3,4-dione; 6-
(Benzyloxy)-9-
(4-methylbenzyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione; 6-(Benzyloxy)-1,9-
dihydropyrano[3,4-b]indole-3,4-dione; 6-(Benzyloxy)-9-(4-tertbutylbenzyl)-1,9-
CA 02643731 2008-08-26
WO 2007/098278 PCT/US2007/005069
dihydropyrano[3,4-b]indole-3,4-dione; 9-(4-tertbutybenzyl)-6-hydroxy-1,9-
dihydropyrano[3,4-
b]indole-3,4-dione; 9-benzyl-6-(4-chlorophenyl)-1,9-dihydropyrano[3,4-b]indole-
3,4-dione;
[1-benzyl-5-(4-chlorophenyl)-2-(hydroxymethyl)-IH-indole-3-yl](oxo)acetic
acid; [1-benzyl-5-
(l,1-biphenyl-4-yl)-2-(hydroxymethyl)-IH-indole-3-yl](oxo)acetic acid; 9-
benzyl-6-(3-
Methylphenyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione; 9-benzyl-6-(1-I-bi-
phenyl-4-yl)-1,9-
dihydropyrano[3,4-b]indole-3,4-dione; or a phanmaceutically acceptable salt,
solvate, or ester
form thereof.
[0042] Methods of synthesizing compounds of formula (XI) are provided in
US20050113436 incorporated herein by reference in its entirety and for all
purposes, and are
thus not described herein.
[00431 In some aspects, this invention describes a method of treating muscle
damage,
muscle wasting, muscle degeneration, muscle atrophy or reduced rate of muscle
repair, wherein
said method comprises the administration of an effective amount of a compound
of formula
(XX), or a pharmaceutically acceptable salt, solvate or ester thereof, to a
mammal in need
thereof
Rs
R8. OH
N
O O
R3 O
R2
N
R~
(XX)
wherein:
Ri is CI-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, pyridinyl, -CH2-
pyridinyl,
phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl
groups are optionally
substituted by from I to 3 groups selected from the group consisting of
halogen, Ci-C6 alkyl, Ci-
C3 perfluoroalkyl, -O-CI -C3 perfluoroalkyl, Ci-C3 alkoxy, -OH, -NH2, and -
NO2;
R2 is hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or CI-C3
perfluoroalkyl;
R3 is hydrogen, halogen, CI-C6 alkyl, CI-C3 perfluoroalkyl, CI-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyl, -IVH2i or -NO2;
R4 is phenyl, benzyl, benzyloxy, pyridinyl, or -CH2-pyridinyl, wherein the
rings of these
groups are optionally substituted by I to 3 groups selected from the group
consisting of halogen,
Ci-C3 alkyl, Ci-C3 perfluoroalkyl, -0-Ci-C3 perfluoroalkyl, CI -C3 alkoxy, -
OH, -NH2, and -NO2;
21
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WO 2007/098278 PCT/US2007/005069
R8 is hydrogen, CI-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, Ci-C3
perfluoroalkyl, aryl, substituted aryl, alkyl-aryl, or substituted alkyl-aryl;
and
R9 is hydrogen, CI -C6 alkyl, C3-C6 branched alkyl; Ci-C6 hydroxyalkyl, 4-
hydroxybenzyl, 3-indolylymethylene, 4-imidazolylmethylene,,HSCH2-, CH3SCH2CH2-
,
H2NC(=O)CH2-, H2NC(=O)CH2CH2-, HO2CCHZ-, HOZCCHzCHZ-, H2NCH2CH2CH2CH2-,
H2NC(=NH)NHCH2CH2CH2-, or taken together with R8, -CH2CH2CH2-;
or a pharmaceutically acceptable salt, solvate, or ester form thereof.
[0044] Exemplary compounds of formula (XX) include those in which R9 is
hydrogen,
Ci-C6 alkyl, C3-C6 branched alkyl, 4-hydroxybenzyl, 3-indolylymethylene, 4-
imidazolylmethylene, -CH3SCH2CH2-, H2NC(=O)CH2-, H2NC(=O)CH2CH2-, HO2CCH2-,
HO2CCH2CH2-, H2NCH2CH2CH2CH2-, H2NC(=NH)NHCH2CH2CH2-, or taken together with
R8, -CHZCH2CHZ-.
[0045] Compounds of formula (XX) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formulas
(XXI) and (XXII):
R9 R9
R8 N ~OH RB~N~OH
R3 O O 0 R3 O O O
.~ ~ R4
~ R2 or R2
R4 N N
iR, Rl
(XXI) (XXII)
wherein Ri, R2, R3, R4, R8 and R9 are as defined herein for a compound of
formula (XX), or a
pharmaceutically acceptable salt, solvate, or ester fonn thereof.
[00461 Compounds of formula (XX) include the following compounds, or
pharmaceutically acceptable salt, solvate or ester forms thereof, of formulas
(XXIII) and
(XXIV):
R Rs
$
O N -( OH R8\ Ry
OH
O O R5 O N
R3 O
J~<' Rs R
R 3 O
R ~ N 2 R7 .~ ( \ R2
N
s or
R / R1
7
(XXIII) (XXIV)
22
CA 02643731 2008-08-26
WO 2007/098278 PCT/US2007/005069
wherein:
R, is Ci-Cg alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or benzyl, wherein
the rings
of the cycloalkyl and benzyl groups are optionally substituted by from I to 3
groups selected
from halogen, Ci-C3 alkyl, Ci-C3 perfluoroalkyl, -O-Ci-C3 perfluoroalkyl,
preferably -0-CF3i
CI-C3 alkoxy, -OH, -NH2, or -NO2;
R2 is hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or Ci-C3
perfluoroalkyl;
R3 is hydrogen, halogen, CI-C6 alkyl, C1-C3 perfluoroalkyl, CI-C6 alkoxy, C3-
C6
cycloalkyl, -CH2-C3-C6 cycloalkyl, -NH2, or -NO2;
R5, R6 and R7 are each independently hydrogen, halogen, CI -C3 alkyl, Ci-C3
perfluoroalkyl, -O-C1-C3 perfluoroalkyl, CI-C3 alkoxy, -OH, -NH2, or -NO2;
Rg is hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, Ci-C3
perfluoroalkyl, aryl, substituted aryl, alkyl-aryl, or substituted- alkyl-
aryl;
R9 is hydrogen, Ci-C6 alkyl, C3-C6 branched alkyl, CI-C6 hydroxyalkyl, 4-
hydroxybenzyl, 3-indolylymethylene, 4-imidazolylmethylene, HSCH2-, CH3SCH2CH2-
,
H2NC(=O)CH2-, H2NC(=O)CH2CH2-, HO2CCH2-, HOZCCH2CH2-, H2NCH2CH2CH2CH2-,
H2NC(=NH)NHCH2CH2CH2-, or taken together with RS, -CH2CH2CH2-; or a
pharmaceutically
acceptable salt or ester form thereof.
[00471 Exemplary compounds of formulas (XXIII) and (XXIV) include those in
which
R9 is hydrogen, Ci-C6 alkyl, C3-C6 branched alkyl, 4-hydroxybenzyl, 3-
indolylymethylene, 4-
imidazolylmethylene, CH3SCH2CH2-, H2NC(=O)CH2-, H2NC(=O)CH2CH2-, HO2CCH2-,
HO2CCH2CH2-, H2NCH2CH2CH2CH2-, H2NC(=NH)NHCH2CH2CH2-, or taken together with
R8, -CH2CH2CH2-.
[0048] Exemplary compounds of formula (XX) include:
{[[1-(4-tert-butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetyl]amino}
acetic acid; 2-
[(2-{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]=1H-indol-3-yl}-2-
oxoacetyl)amino]acetic acid; 2-
[(2- { 1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl} -2-
oxoacetyl)(methyl)amino]acetic
acid; or a pharmaceutically acceptable salt or ester form thereof.
100491 Methods of synthesizing compounds of formula XX are provided in US
Publication Number 20040116504 incorporated herein by reference in its
entirety and for all
purposes, and are thus not described herein.
[00501 The present invention provides, inter alia, pharmaceutical compositions
useful
for the treatment of muscle damage, muscle wasting, muscle degeneration,
muscle atrophy or
reduced rate of muscle repair, wherein said pharmaceutical compositions
comprise a PAI-1
23
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WO 2007/098278 PCT/US2007/005069
inhibitor. In certain aspects the PAI-1 inhibitors useful for the methods of
this invention have a
molecular weight of less than 1,000. Exemplary PAI-1 inhibitors include those
compounds
described herein, for example, the compounds of formulas (I) - (XXIV) or
pharmaceutically
acceptable salt, solvate, or ester forms thereof.
[00511 The present invention provides, inter alia, methods for the treatment
of muscle
damage, muscle wasting, muscle degeneration, muscle atrophy or reduced rate of
muscle repair,
wherein said method comprises the administration of a pharmaceutical
composition comprising a
PAI-1 inhibitor to a mammal in need thereof. In certain aspects the PAI-1
inhibitors useful for
the methods of this invention have a molecular weight of less than 1,000. In
exemplary
embodiments of the present invention, the compounds and compositions of the
present invention
are used to increase muscle weight, i.e., skeletal muscle weight, in manunals
in need thereof, i.e.,
in mammals having a condition characterized by muscle damage, muscle wasting,
muscle
degeneration, muscle atrophy or reduced rate of muscle repair.
100521 In some aspects, the PAI-1 inhibitors useful in compositions for the
methods of
this invention are described in US20060014725, US20050215626, US20050119327,
US20050119326, US20050119296, US20050113439, US20050113438, US20050113438,
US20050113436, US20050113428, US20050096377, US20050070592, US20050070587,
US20050070585, US20050070584, US20040266733, US20040138283, US20040122070,
US20040116504, US20040116488, US20030125371, US20030045560, US20030032626,
US20030018067, and US20030013732, which are herein incorporated by reference
in their
entirety.
100531 The present invention provides, inter alia, pharmaceutical compositions
useful
for the treatment of muscle damage, muscle wasting, muscle degeneration,
muscle atrophy or
reduced rate of muscle repair, wherein said composition comprises an effective
amount of the
compounds of the present invention including the compounds of formulas (I) -
()OXIV), and at
least one pharmaceutically acceptable excipient.
[0054] In some embodiments, this invention describes a pharmaceutical
composition
useful for the treatment of muscle damage, muscle wasting, muscle
degenerationõ muscle atrophy
or reduced rate of muscle repair, wherein said composition comprises an
effective amount of
formula: {1-Methyl-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic
acid; {1-Methyl-
6-[4-(trifluoromethyl)phenyl]-1 H-indol-3-yl} (oxo)acetic acid; { 1-Ethyl-6-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;{1-Ethyl-6-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-Benzyl-6-[4-
(trifiuoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;{1-Benzyl-6-[4-
24
CA 02643731 2008-08-26
WO 2007/098278 PCT/US2007/005069
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {1-[4-(tert-
Butyl)benzyl]-6-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid;{I-[4-(tert-
Butyl)benzyl]-6-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid;{1-Benzyl-5-[4-
(trifluoromethyl)phenyl]-1 H-indol-3-yl} (oxo)acetic acid; {6-[4-(tert-
Butyl)phenyl]-I-methyl-IH-
indol-3-yl}(oxo)acetic acid; [5-(4-Acetylphenyl)-1-benzyl-lH-indol-3-
yl](oxo)acetic acid;{1-
Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; {I-
Benzyl-4-[4-
(trifluoromethyl)phenyl]-1H-indol-3-yi}(oxo)acetic acid;{1-Benzyl-5-[4-(tert-
butyl)phenyl]-1H-
indol-3-yl} (oxo)acetic acid; [1-Benzyl-5-(3-chloro-4-fluorophenyl)-1 H-indol-
3-yl](oxo)acetic
acid; { 1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1 H-indol-3-yl}
(oxo)acetic acid; { 1-Benzyl-7-
[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; [1-Benzyl-7-(3-
chloro-4-
fluorophenyl)-1H-indol-3-yl](oxo)acetic acid; {1-(4-tert-Butylbenzyl)-5-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; { 1-Benzyl-4-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; [1-Benzyl-6-(3-
chlorophenyl)-1H-
indol-3-yl](oxo)acetic acid; { 1-Benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-
indol-3-yl}(oxo)acetic
acid; { 1-(4-Methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}
(oxo)acetic acid; {1-(4-
Fluorobenzyl)-5-[4-(trifluoromethoxy)phenyll-lH-indol-3-yl}(oxo)acetic acid;[1-
Butyl-5-(4-
chlorophenyl)-1H-indol-3-yi](oxo)acetic acid; [1-Butyl-5-(3-chlorophenyl)-1H-
indol-3-
yl](oxo)acetic acid; [I-Butyl-5-(3-methoxyphenyl)-1H-indol-3-yl](oxo)acetic
acid; [1-Butyl-5-
(4-methoxyphenyl)-1 H-indol-3-yl](oxo)acetic acid; { 1-Butyl-5-[4-
(trifluoromethyl)phenyl]-1 H-
indol-3-yl}(oxo)acetic acid; [ 1-(4-tert-Butylbenzyl)-5-(3-methylphenyl)-1H-
indol-3-
y1](oxo)acetic acid; [1-(4-tert-Butylbenzyl)-5-(3-methoxyphenyl)-1H-indol-3-
yl](oxo)acetic
acid; [1-(4-tert-Butylbenzyl)-5-(4-tert-butylphenyl)-1H-indol-3-y1](oxo)acetic
acid; [1-(4-tert-
Butylbenzyl)-5-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid; [1-(4-tert-
Butylbenzyl)-5-(4-
chlorophenyl)-1H-indol-3-yl](oxo)acetic acid; [1-(4-tert-Butylbenzyl)-5-(2-
methylphenyl)-1H-
indol-3-yl](oxo)acetic acid; { 1-(2-Ethylbutyl)-5-[4-(trifluoromethoxy)phenyl]-
1 H-indol-3-_
yl}(oxo)acetic acid;{2-[(Acetyloxy)methyl]-1-(4-methylbenzyl)-5-[4-
(trifluoromethoxy)phenyl]-
1 H-indol-3-yl } (oxo)acetic acid; {2-(Hydroxymethyl)-1-(4-methylbenzyl)-5-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl} (oxo)acetic acid; {2-
[(Acetyloxy)methyl]-1-benzyl-5-
[4-(trifluoromethoxy)phenyl]-1 H-indol-3-yl} (oxo)acetic acid; { 1-Benzyl-2-
(hydroxymethyl)-5-
[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid; [5-(3-
Chlorophenyl)-1-
cyclopentyl-lH-indol-3-yl]-oxo-acetic acid; [5-(3-chlorophenyl)-1-
(cyclobutylmethyl)-1 H-indol-
3-yl](oxo)acetic acid; [5-(3-chlorophenyl)-1-(3-methylcyclopropyl)-1H-indol-3-
yl](oxo)acetic
acid; [5-(3-chlorophenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid;
[5-(4-
trifluoromethylphenyl)-1-(cyclopentyl)-l H-indol-3-yl](oxo)acetic acid; [5-(4-
CA 02643731 2008-08-26
WO 2007/098278 PCT/US2007/005069
trifluoromethylphenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid; [5-
(4-
trifluoromethylphenyl)-1-(3-methylcyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
[5-(4-
trifluoromethylphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid; [5-
(4-
trifluoromethylphenyl)-1-(cyclopentylpropyl)-1 H-indol-3-yl](oxo)acetic acid;
[5-(3-
trifluoromethylphenyl)-1-(cyclopentyl)-1H-indol-3-yl](oxo)acetic acid; [5-(3-
trifluoromethylphenyl)-1-(cyclobutylmethyl)-1H-indol-3-yl](oxo)acetic acid; [5-
(3-
trifluoromethylphenyl)-1-(3-methylcyclopentyl)-1H-indol-3-yl](oxo)acetic acid;
[5-(3-
trifluoromethylphenyl)-1-(cyclohexylmethyl)-1H-indol-3-yl](oxo)acetic acid; [5-
(3-
trifluoromethylphenyl)-1-(cyclopentylpropyl)-1H-indol-3-yl](oxo)acetic acid;
or [5-(4-
methoxyphenyl)-1-(cyclohexylmethyl)-1 H-indol-3-yl](oxo)acetic acid; [3-(4-
chlorobenzoyl)-5-
(4-chlorophenyl)-IH-indol-l-yl]acetic acid; [3-(Benzo[b]thiophene-2-carbonyl)-
5-(4-
methylphenyl)-IH-indol-l-yl]-acetic acid; [3-(4-chlorobenzoyl)- 5-(4-
methylphenyl)-1H-indol-
1-yl]-acetic acid; {5-(3-trifluoromethoxyphenyl)-3-[1-(4-
trifluoromethylphenyl)-ethyl]-indol-l-
yl}-acetic acid; {3-[3,5-bis(trifluoromethyl)benzyl]-5-[4-
(trifluoromethoxy)phenyl]-1H-indol-l-
yl} acetic) acid; [3-[3,5-bis(trifluoromethyl)benzyl]-5-(2,4-dichlorophenyl)-
1H-indol-l-yl]acetic
acid; {3-[3,5-bis(trifluoromethyl)benzyl]-5-[3-(trifluoromethyl)phenyl]-IH-
indol-l-yl}acetic
acid; {5-(3-chlorophenyl)-3-[1-(2-thienyl)ethyl]-1H-indol-1-yl}acetic acid; [3-
(1-phenylethyl)-5-
(3-tri fluoromethyl-phenyl)-indol-l-yl]acetic acid; [3-(1-thiophen-2-yl-ethyl)-
5-(3-
trifluoromethyl-phenyl)-indol-1-yl]acetic acid; [3-(1-cyclohexyl-ethyl)-5-(3-
trifluoromethyl-.
phenyl)-indol-l-yl]acetic acid; [3-(4-isopropyl-benzyl)-5-(3-trifluoromethyl-
phenyl)-indol-l-
ylJacetic acid; [5-(2,4-dichloro-phenyl)-3-(1,3-dimethyl-butyl)-indol-1-yl]-
acetic acid; [5-(2,4-
dichloro-phenyl)-3-(1-phenyl-ethyl)-indol-l-yl]-acetic acid; [3-(1-cyclohexyl-
ethyl)-5-(2,4-
dichloro-phenyl)-indol-l-yl]-acetic acid; (1-{4-[(4-cyanobenzyl)oxy]phenyl}-1H-
indol-3-
yl)(oxo)acetic acid; {1-[4-(3-methoxy-benzyloxy)-phenyl]1H-indol-3-yl}-oxo-
acetic acid; {1-[4-
(3-chloro-benzyloxy)-phenyl] 1H-indol-3-yl}-oxo-acetic acid; { 1-[4-(4-
cyanobenzyloxy)-
phenyl]-5-fluoro-lH-indol-3-yl}-oxo-acetic acid; { 1-[4-(3,5-dimethoxy-
benzyloxy)-phenyl]-5-
fluoro-lH-indol-3-yl}-oxo-acetic acid; {1-[4-(3-chloro-benzyloxy)-phenyl]-5-
niethyl-lH-indol-
3-yl}-oxo-acetic acid; {1-[4-(2,4-dichlorobenzyloxy)-phenyl]-5-methyl-lH-indol-
3-yl}-oxo-
acetic acid; {5-Chloro-l-[3-(4-cyano-benzyloxy)-phenyl]1H-indol-3-yl}-oxo-
acetic acid; {5-
Chloro-l-[3-(3,5-dimethoxy benzyloxy)-phenyl]1H-indol-3-yl}-oxo-acetic acid;
{1-[4-(2,3,5,6-
tetrafluoro-4-trifluoromethyl-benzyloxy)-phenyl]1H-indol-3-yl}-oxo-acetic
acid; {1-[4-(2,6-
dichloro-pyridin-4-ylmethoxy)-phenyl]1H-indol-3-yl}-oxo-acetic acid; [1-(4-{[5-
(ethoxycarbonyl)-2-furyl]methoxy}phenyl)-5-fluoro-lH-indol-3- yl](oxo)acetic
acid; (1-[4-(2,6-
dichloropyridin-4-ylmethoxy)-phenyl]-5-methyl-lH-indol-3-yl}-oxo-acetic acid;
{5-Chloro-l-
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WO 2007/098278 PCT/US2007/005069
[3-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzyloxy)-phenyl]1H-indol-3-yl}-oxo-
acetic acid; [5-
chloro-l-(3-{[5-(ethoxycarbonyl)-2-furyl]methoxy}phenyl)-1H-indol-3-
yl](oxo)acetic acid; 5-
Chloro-l-[3-(2,6-dichloro-pyridin-4-ylmethoxy)-phenyl]1H-indol-3-yl}-oxo-
acetic acid; [1,5-
bis-(4-trifluoromethoxy-phenyl)-1H-indol-3-yl]-oxo-acetic acid; [1,5-bis-(4-
trifluoromethoxy-
phenyl)-1H-indol-3-yl]-oxo-acetic acid;{1-(4-fluorobenzyl)-5-[2-(4-
fluorophenyl)ethoxy]-]H-
indol-3-yl}(oxo)acetic acid, [1-benzyl-5-(2-chloro-4-trifluoromethyl-phenoxy)-
]H-indol-3-yl]
(oxo)acetic acid; (1-benzyl-5-benzyloxy-lH-indol-3-yl)-oxo-acetic acid; (5-
allyloxy-l-
cyclobutylmethyl-1 H-indol-3-yl)-oxo-acetic acid; (5-allyloxy-l-phenethyl-lH-
indol-3-yl)-oxo-
acetic acid; (5-allyloxy-l-benzo[1,3]dioxol-5-ylmethyl-lH-indol-3-yl)-oxo-
acetic acid; (5-
allyloxy-l-[2-(4-methoxyphenyl)-ethyl]-1H-indol-3-yl)-oxo-acetic acid; (5-
allyloxy-l-[2-
naphthalene-l-yl-ethyl]-1H-indol-3-yl)-oxo-acetic acid; (5-allyloxy-l-[2-(3-
trifluoromethylphenyl)-ethyl]-1 H-indol-3-yi)-oxo-acetic acid; (5-allyloxy-l-
[2-(4-bromophenyl)-
ethyl]-1H-indol-3-yl)-oxo-acetic acid; {1-[4-(4-tert-butyl-benzyloxy)-phenyl]-
5-methyl-IH-
indol-3-yl}-oxo-acetic acid; { 1-[4-(4-[1,2,3]thiadiazol-4-yl-benzyloxy)-
phenyl]-1H-indol-3-yl}-
oxo-acetic acid; {5-Chloro-l-[3-(4-[1,2,3]thiadiazol-4-yl-benzyloxy)-phenyl]1H-
indol-3-yl}-
oxo-acetic acid; 9-(4-Methylbenzyl)-6-[4-(trifluoromethoxy)phenyl]-1,9-
dihydropyrano[3,4-
b]indole-3,4-dione; 9-Benzyl-6-[4-(trifluoromethoxy)phenyl]-1,9-
dihydropyrano[3,4-b]indole-
3,4-dione; 9-(4-Methylbenzyl)-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-
b]indole-3,3-dione;
9-(4-tert-butylbenzyl)-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-b] indole-3,4-
dione; 6-
(Benzyloxy)-9-(4-methylbenzyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione; 6-
(Benzyloxy)-1,9-
dihydropyrano[3,4-b]indole-3,4-dione; 6-(Benzyloxy)-9-(4-tertbutylbenzyl)-1,9-
dihydropyrano[3,4-b]indole-3,4-dione; 9-(4-tertbutybenzyl)-6-hydroxy-l,9-
dihydlropyrano[3,4-
b] indole-3,4-dione; 9-benzyl-6-(4-chlorophenyl)-1,9-dihydropyrano[3,4-
b]indole-3,4-dione;
[ 1-benzyl-5-(4-chlorophenyl)-2-(hydroxymethyl)-1H-indole-3-yl](oxo)acetic
acid; [ 1-benzyl-5-
(1,1-biphenyl-4-yl)-2-(hydroxymethyl)-1H-indole-3-yl](oxo)acetic acid; 9-
benzpl-6-(3-
Methylphenyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione; 9-benzyl-6-(1-1-bi-
ptaonyl-4-yl)-1,9-
dihydropyrano[3,4-b]indole-3,4-dione; {[[1-(4-tert-butylbenzyl)-5-(3-
methylphemyl)-1H-indol-3-
yl](oxo)acetyl]amino}acetic acid; 2-[(2-{1-Benzyl-5-[4-
(trifluoromethoxy)phenyt]-1H-indol-3-
yl}-2-oxoacetyl)amino]acetic acid; 2-[(2-{1-Benzyl-5-[3-
(trifluoromethoxy)pherayl]-1H-indol-3-
yl}-2-oxoacetyl)(methyl)amino]acetic acid; or a pharmaceutically acceptable
sa1S. solvate or
ester thereof, and at least one pharmaceutically acceptable excipient.
[0055] In some embodiments of this invention, the compositions of this;
invention are in
the form of a tablet or capsule. '
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WO 2007/098278 PCT/US2007/005069
[0056] In some embodiments, this invention describes a pharmaceutical
composition
useful for the treatment of muscle wasting, muscle degeneration, muscular
atrophy, or reduced
rate of muscle repair, wherein said muscle wasting, muscle degeneration,
muscular atrophy, or
reduced rate of muscle repair is caused by or associated with muscular
dystrophy.
[0057] In some embodiments, this invention describes a pharmaceutical
composition
useful for the treatment of muscle wasting, muscle degeneration, muscular
atrophy, or reduced
rate of muscle repair caused by or associated with muscular dystrophy of the
type Duchenne's,
Becker's, distal, ocular, Emery-Dreifuss, facioscapulohumeral, Fukuyama
congenital, limb-
girdle, myotonic, oculopharyngeal or severe childhood autosomal recessive.
[0058] Using the methods of the present invention, one or more compounds or
phannaceutical compositions of the present invention can be administered
concomitantly with
other known therapies to treat a subject suffering muscle wasting, muscle
degeneration, muscular
atrophy, or reduced rate of muscle repair. "Concomitant administration" of a
known therapy
with a pharmaceutical composition of the present invention means
administration of the drug and
the pharmaceutical composition at such time that both the known drug and the
composition of
the present invention will have a therapeutic effect. Such concomitant
administration can
involve concurrent (i.e. at the same time), prior, or subsequent
administration of the known
therapy with respect to the administration of a coinpound of the present
invention. A person of
ordinary skill in the art, would have no difficulty determining the
appropriate timing, sequence
and dosages of administration for particular drugs and compositions of the
present invention.
For example, in some embodiments, the compounds of this invention can be used
in combination
with an agent that decreases the efficacy of endogenous myostatin for the
treatment of muscular
dystrophy.
[0059] In some embodiments, the compounds of this invention can be used in
combination with a myostatin antibody for the treatment of muscular dystrophy.
100601 In certain embodiments, the compounds of this invention can be used in
combination with prothrombolytic and fibrinolytic agents, which include, but
are not limited to
tissue plasminogen activator, streptokinase, and activase for the treatment of
muscular
dystrophy.
[0061] In some embodiments of this invention, said method of treating muscular
dystrophy further comprises the administration of at least one anabolic agent,
including, for
example, an anabolic androgen.
(0062] In some embodiments of this invention, said method of treating muscular
dystrophy further comprises the administration of a glucocorticoid.
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WO 2007/098278 PCT/US2007/005069
[0063] The preferred salt forms of the compounds herein include but are not
limited to
sodium salts, and potassium salts. Other useful salt forms of these compounds
include those
formed with pharmaceutically acceptable inorganic and organic bases known in
the arr_ Salt
forms prepared using inorganic bases include hydroxides, carbonates or
bicarbonates of the
therapeutically acceptable alkali metals or alkaline earth methals, such as
sodium potassium,
magnesium, calcium and the like. Acceptable organic bases include amines, such
as
benzylzmine, mono-, di- and trialkylamines, preferably those having alkyl
groups of from 1 to 6
carbon atoms, more preferably I to 3 carbon atoms, such as methylamine,
dimethylamine,
trimethylamine, ethylamine, diethylamine, triethylamine, mono-, di-, and
triethanolamine. Also
useful are alkylene diamines containing up to 6 carbon atoms, such as
hexamethylenedhamine;
cyclic saturated or unsaturated bases containing up to 6 carbon atoms,
including pyrrolidine,
peperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl
derivatives, such as N-
methyl-morpholine and N-(2-hyroxyethyl)-piperidine, or pyridine. Quaternary
salts can also be
formed, such as tetralkyl forms, such as tetramethyl forms, alkyl-alkanol
forms, such as methyl-
triethanol or trimethyl-monoethanol forms, and cyclic ammonium salt forms,
such as N-
methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-di-
methylmorpholinium,
N-methyl-N-(2-hydroxyethyl)-morpholinium, or N,N-dimethyl-piperidinium salt
forms. These
salt forms can be prepared using the acidic compound(s) of the formulas
described herein and
procedures known in the art.
[00641 The compounds used in the methods of this invention can contain one or
more
asymmetric centers, which can thus give rise to optical isomers (enantiomers)
and diastereomers.
The present invention includes such optical isomers (enantiomers) and
diastereomers (geometric
isomers); as well as the racemic and resolved, enantiomerically pure R and S
stereoisomers; as
well as other mixtures of the R and S stereoisomers and pharmaceutically
acceptable salts
thereof. The use of these compounds is intended to cover the racemic mixture
or either of the
chiral enantiomers.
[0065] Optical isomers can be obtained in pure form by standard procedures
known to
those skilled in the art, and include, but are not limited to, diastereomeric
salt formation, kinetic
resolution, and asymmetric synthesis. See, for example, Jacques, et al.,
Enantiomers, Racemates
and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al.,
Tetrahedron 33:2725
(1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
1962); Wilen,
S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel,
Ed., Univ. of Notre
Dame Press, Notre Dame, IN 1972), each of which is incorporated herein by
reference in their
entireties. It is also understood that this invention encompasses all possible
regioisomers, and
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WO 2007/098278 PCT/US2007/005069
mixtures thereof, which can be obtained in pure form by standard separation
procedures known
to those skilled in the art, and include, but are not limited to, column
chromatography, thin-laycr
chromatography, and high-performance liquid chromatography.
[0066] One skilled in the art will also recognize that it is possible for
tautomers to exist
for the compounds of the present invention. The present invention includes all
such tautomers
even though not shown in the fonmulas herein.
[0067] Compounds of the invention can also include all isotopes of atoms
occurring in
the intermediates or final compounds. Isotopes include those atoms having the
same atomic
number but different mass numbers. For example, isotopes of hydrogen include
tritium and
deuterium.
[0068] Ester forms of the compounds of this invention include straight chain
alkyl
esters having from I to 6 carbon atoms or brariched chain alkyl groups
containing 3 or 6 carbon
atoms, including methyl, ethyl, propyl, butyl, 2-methylpropyl and 1,1-
dimethylethyl esters.
Other esters useful with this invention include those of the formula -COORg
wherein Rs is
selected from the formulae:
O
12
OY R1 N 11-1 R
Y
Rg 0 or
Rll
(~) (2)
wherein R9, RIo, R>>, R12 are independently selected from hydrogen, alkyl of
from I to 10 carbon
atoms, aryl of 6 to 14 carbon atoms, arylalkyl of from 6 to 14 carbon atoms
wherein the aryl ring
is bound by an alkyl chain of from 1 to 6 carbon atoms; heteroaryl or
alkylheteroaryl wherein the
heteroaryl ring is bound by an alkyl chain of from 1 to 6 carbon atoms.
100691 Among the preferred ester forms of the compounds herein include but not
limited to Ci-C6 alkyl esters, C3-C6 branched alkyl esters, benzyl esters, and
the like.
[0070] As used herein, "aryl", employed alone or in combination with other
terms,
refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon
atoms having a single
ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or
anthryl). Preferred aryl
groups include phenyl, naphthyl and the like. As used herein, "heteroaryl",
employed alone or in
combination with other terms, refers to a monocyclic or bicyclic aromatic
group of from about 5
to about 14 carbon atoms and 1 to about 4 heteroatoms selected from oxygen,
nitrogen and sulfur
within at least one ring (if there is more than one ring). Such heteroaryl
groups can have a single
ring, such as pyridyl, pyrrolyl or furyl groups, or multiple condensed rings,
such as indolyl,
CA 02643731 2008-08-26
WO 2007/098278 PCT/US2007/005069
indolizinyl, benzofuranyl or benzothienyl groups. Preferred heteroaryls
include pyridyl, pyrrolyl
and furyl.
[00711 Unless otherwise limited by the definition for the aryl or heteroaryl
groups
herein, such groups can optionally be substituted with from l to 5
substituents selected from the
group consisting of acyloxy, hydroxy, acyl, alkyl of I to 6 carbon atoms,
alkoxy of 1 to 6 carbon
atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,
substituted alkyl of I to 6
carbon atoms, substituted alkoxy of I to 6 carbon atoms, substituted alkenyl
of 2 to 6 carbon
atoms, substituted alkynyl of 2 to 6 carbon atoms, amino, amino substituted by
one or two alkyl
groups of from I to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo,
nitro, thioalkoxy
of from I to 6 carbon atoms, substituted thioalkoxy of from I to 6 carbon
atoms, and
trihalomethyl. Substituents on the alkyl, alkenyl, alkynyl, thioalkoxy and
alkoxy groups
mentioned above include halogens, CN, OH, and amino groups. Preferred
substituents on the
aryl groups herein include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,
and thioalkoxy.
100721 The term "alkyl", employed alone or in combination with other terms,
refers to a
saturated hydrocarbon group that can be straight-chain or branched. In some
embodiments, the
alkyl group contains within the range of carbons specified and in some
embodiments where not
otherwise specified, the alkyl group contains I to 10 carbon atoms, preferably
1 to 6 carbon
atoms. Examples of alkyl moieties include, but are not limited to, chemical
groups such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl;
higher homologs such
as 2-methyI-l-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and
the like.
100731 The term "alkenyl", as used herein, whether used alone or as part of
another
group, refers to an aliphatic hydrocarbon chain and includes, but is not
limited to, straight and
branched chains having 2 to about 10 carbon atoms (unless explicitly specified
otherwise) and
containing at least one double bond. Preferably, the alkenyl moiety has I or 2
double bonds.
Preferably, the alkenyl moiety has about 2'to about 7 carbon atoms. Such
alkenyl moieties can
exist in the E or Z conformations and the compounds of this invention include
both
conformations.
[0074] The term "alkynyl", as used herein, whether used alone or as part of
another
group, refers to an aliphatic hydrocarbon chain and includes, but is not
limited to, straight and
branched chains having 2 to about 10 carbon atoms (unless explicitly specified
otherwise) and
containing at least one triple bond. Preferably, the alkynyl moiety has about
2 to about 7 carbon
atoms. In certain embodiments, the alkynyl can contain more than one triple
bond and, in such
cases, the alkynyl group must contain at least four carbon atoms.
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WO 2007/098278 PCT/US2007/005069
[0075] The ten~n "perfluoroalkyl", as used herein, whether used alone or as
part of
another group, refers to a saturated aliphatic hydrocarbon having I to 6
carbon atoms and two or
more fluorine atoms and includes, but is not limited to, straight or branched
chains, such as -CF3,
-CH2CF3, -CF2CF3 and -CH(CF3)2.
100761 The term "halogen" or "halo" refers to chlorine, bromine, fluorine, and
iodine.
[0077] As used herein, the term "cycloalkyl", employed alone or in combination
with
other tenns, refers to a non-aromatic cyclic hydrocarbon moiety. Cycloalkyl
groups can be
characterized as having a range of carbon atoms as specified and one or more
backbone carbon
atoms of the cycloalkyl group can be double-bonded to an oxygen atom.
Cycloalkyl groups have
about 3 to about 20 carbon atoms, preferably 3 to about 6 carbon atoms.
Exemplary cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexanone and
cyclohexyl.
[0078] As used herein, the term "cycloalkenyl", refers to a non-aromatic
cyclic
hydrocarbon moiety containing I or more double bonds within the backbone
structure of the
cycloalkene moiety. Cycloalkenyl groups can be characterized as having a range
of carbon
atoms as specified and one or more backbone carbon atoms of the cycloalkenyl
group can be
double-bonded to an oxygen atom.
[0079] The tenn "acyl", employed alone or in combination with other tenns, is
defined
herein as, unless otherwise stated, either an alkyl, arylalkyl, -
heteroarylalkyl, (C2-C10) straight
chain, or (C4-Cl 1) branched-chain monovalent hydrocarbon moiety; wherein the
carbon atom,
covalently linked to the defined chemical structure, is oxidized to the
carbonyl oxidation state.
.Such hydrocarbon moieties may be mono or polyunsaturated, and may exist in
the E or Z
configurations. Examples of acyl moieties include, but are not limited to,
chemical groups such
as acetyl, propionyl, butyryl, 3,3-dimethylbutyryl, trifluoroacetyl, pivaloyl,
hexanoyl, hexenoyl,
decanoyl, benzoyl, nicotinyl, isonicotinyl, and homologs, isomers, and the
like.
[0080] Exemplary compounds of this invention are active as PAI-1 inhibitors.
In
inhibiting PAI-1, the compounds can effectively increase the amount of
plasminogen, plasmin
and thus enhance fibrinolysis. While not wishing to be bound by theory, it is
believed that the
compounds of this invention prevent muscle wasting and facilitate muscle
damage repair via
inhibition of the plasminogen activator inhibitor 1. In so doing, increased
levels of plasminogen
are available in turn generating increased levels of plasmin. Such increased
levels of plasmin
can increase muscle healing processes via clearance of fibrin clots thus
allowing cell migration to
the muscle injury site and a corresponding increased rate of muscle repair.
Exemplary
compounds of this invention have broad applicability to conditions associated
with rnuscle
damage, wasting, degeneration, atrophy or reduced rate of repair. Such
conditions can come
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WO 2007/098278 PCT/US2007/005069
about as a result of other conditions, for example, diabetes, hyperglycemia,
motor neuron
diseases, carpal tunnel syndrome, chronic infection, tuberculosis, Addison's
disease, adult spinal
muscular atrophy, anorexia nervosa, dermatomyositis, inclusion body myositis,
incontinentia
pigmenti, intercoastal neuralgia, juvenile rheumatoid arthritis, legg-calve-
perthes disease,
multi focal motor neuropathy, nephritic syndrome, osteogenesis imperfecta,
post-polio syndrome,
spinal muscular atrophy, nerve injury, neuropathy, diabetic neuropathy,
alcoholic neuropathy,
and muscular dystrophy.
100811 Exemplary compounds of this invention are useful for the treatment of
muscle
wasting that occurs from immobility and bed rest. Exemplary compounds of this
invention are
useful in treating damage to muscle tissue, wherein such damage may be normal
damage or
traumatic damage. Nonmal damage can occur through routine physical exercise
and movement.
Traumatic damage may occur where muscles are torn, stretched or otherwise
harmed in a violent
or sudden fashion.
[00821 Muscular dystrophy, as referred to herein, refers to the various forms
of
muscular dystrophy including Duchenne's, Becker's, distal, congenital, ocular,
distal, Emery-
Dreifuss, facioscapulohumeral, Fukuyama congenital, limb-girdle, myotonic,
oculopharyngeal
and severe childhood autosomal recessive.
[00831 Methods for the treatment, inhibition, prevention or prophylaxis in a
mammal of
each of the conditions or maladies listed as well as any and all associated
with muscular
dystrophy are part of the present invention. Each method comprises
administering to a mammal
in need thereof a pharmaceutically or therapeutically effective amount of a
compound of this
invention, or a pharmaceutically acceptable salt or ester or solvate form
thereof. The term
"treating" refers to any indicia of success in the treatment or amelioration
or prevention of a
disease, including any objective or subjective parameter such as abatement;
remission;
diminishing of symptoms or making the disease condition more tolerable to the
patient; slowing
in the rate of degeneration or decline; or making the final point of
degeneration less debilitating.
The treatment or amelioration of symptoms can be based on objective or
subjective parameters.
Accordingly, the term "treating" includes the administration of the compounds
or agents of the
present invention to prevent or delay, to alleviate, or to arrest or inhibit
development of the
symptoms or conditions associated with the disease. The term "therapeutic
effect" refers to the
reduction, elimination, or prevention of the disease, symptoms of the disease,
or side effects of
the disease in the subject.
100841 For purposes of this invention, the term "pharmaceutically acceptable
excipient"
includes any pharmaceutically acceptable substance beside the drug substance
(a compound of
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WO 2007/098278 PCT/US2007/005069
one of the formulae of this invention) including diluents, fillers and bulking
agents, binders and
adhesives, propellants, disintegrants, lubricants and glidants, colors,
flavors, coating agents,
polishing agents, fragrances, sweetening agents, polymers, and waxes_
[0085] In some embodiments of this invention, said muscle damage, muscle
wasting,
muscle degeneration, muscle atrophy or reduced rate of muscle repair is caused
by or associated
with diabetes, hyperglycemia, motor neuron diseases, carpal tunnel syndrome,
chronic infection,
tuberculosis, Addison's disease, adult spinal muscular atrophy, anorexia
nervosa,
dermatomyositis, inclusion body myositis, incontinentia pigmenti, intercoastal
neuralgia,
juvenile rheumatoid arthritis, legg-calve-perthes disease, multifocal motor
neuropathy, nephritic
syndrome, osteogenesis imperfecta, post-polio syndrome, spinal muscular
atrophy, nerve injury,
neuropathy, diabetic neuropathy, or alcoholic neuropathy.
[0086] In some embodiments of this invention, said muscle damage is associated
with
normal muscle exertion or exercise.
[0087] In some embodiments of this invention, said muscle damage is associated
with
traumatic injury to muscle.
[0088] In some embodiments of this invention, said muscle wasting, muscle
degeneration, muscular atrophy, or reduced rate of muscle repair is caused by
or associated with
muscular dystrophy.
.[0089] In some embodiments of this invention, said muscular dystrophy is
Duchenne's,
Becker's, distal, ocular, Emery-Dreifuss, facioscapulohumeral, Fukuyama
congenital, limb-
girdle, myotonic, oculopharyngeal or severe childhood autosomal recessive.
[0090] In some embodiments of this invention, said muscular dystrophy is
Duchenne's.
[0091] This invention provides pharmaceutical compositions for use in the
methods of
this invention comprising a pharmaceutically or therapeutically effective
amount of a compound
of this invention, or a pharmaceutically acceptable salt or ester or solvate
form thereof, either
alone or in combination with one or more pharmaceutically acceptable carriers
or excipients (i.e.
pharmaceutically acceptable materials with no significant pharmacological
effects on their own).
It will be understood that a phanmaceutically or therapeutically effective
amount of a compound
herein refers to an amount of the compound in question which will sufficiently
inhibit the serine
protease inhibitor PAI-1 in the mammal in need thereof to a sufficient extent
to provide a
desirable improvement in the condition in question or provide sufficient
inhibition of the serine
protease inhibitor PAI-1 to prevent, inhibit or limit the onset of the
physiological basis for the
malady or condition in question.
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[0092] The precise dosage to be employed depends upon several factors
including the
host, whether in veterinary medicine or human medicine, the nature and
severity of the condition
being treated, the mode of administration and the particular active substance
employed. The
compounds can be administered by any conventional route, in particular
enterally, preferably
orally in the form of tablets or capsules. Administered compounds can be in
the free form or
pharmaceutically acceptable salt form as appropriate, for use as a
pharmaceutical, particularly for
use in the muscle conditions. These measures will slow the rate of progress of
the disease state
and assist the body in reversing the process direction in a natural manner.
[0093] Any suitable carrier known to the art can be used to prepare the
pharmaceutical
compositions. In such a composition, the carrier can be a solid, liquid or
mixture of a solid and a
liquid. Solid compositions include powders, tablets and capsules. A solid
carrier can be one or
more substances which can also act as a flavoring agent, lubricant,
solubilizer, suspending agent,
binder, or tablet disintegrant. In powders, the carrier is a finely divided
solid, which is in
admixture with the finely divided active ingredient. In tablets, the active
ingredient is mixed
with a carrier having the necessary binding properties in suitable proportions
and compacted in
the shape and size desired. Suitable solid carriers are magnesium carbonate,
magnesium stearate,
talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl
cellulose, hydroxymethyl
cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter,
and the 4ike.
Encapsulating materials can also be employed with the compounds of this
invention, and the
term "composition" is intended to include the active ingredient in combination
with an
encapsulating material as a formulation, with or without other carriers.
Cachets can also be used
in the delivery of the medicaments of this invention.
100941 Sterile liquid compositions include solutions, suspensions, emulsions,
syrups
and elixirs. The compounds of this invention can be dissolved or suspended in
the
pharmaceutically acceptable carrier, such as sterile water, sterile organic
solvent or a mixture of
both. Preferably the liquid carrier is one suitable for parental injection.
Where the compounds
are sufficiently soluble they can be dissolved directly in normal saline with
or without the use of
suitable organic solvents, such as propylene glycol or polyethylene glycol. If
desired,
dispersions of the finely divided compounds can be made-up in aqueous starch
or sodium
carboxymethyl cellulose solution, or in a suitable oil, such as arachis oil.
Liquid pharmaceutical
compositions, which are sterile solutions or suspensions, can be utilized by
intramuscular,
intraperitoneal or subcutaneous injection. In many instances a liquid
composition form can be
used instead of the preferred solid oral method of administration.
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[0095] It is preferred to prepare unit dosage forms of the compounds for
standard
administration regimens. In this way, the composition can be subdivided
readily into smaller
doses at the physician's direction. For example, unit dosages can be made up
in packeted
powders, vials or ampoules and preferably in capsule or tablet form. The
active compound
present in these unit dosage forms of the composition can be present in an
amount of from about
one gram to about fifteen grams or more, for single or multiple daily
administration, according to
the particular need of the patient. The daily dose of active compound will
vary depending upon
the route of administration, the size, age and sex of the patient, the
severity of the disease state,
and the response to the therapy as traced by blood analysis and the patients
recovery rate. By
initiating_ the treatment regimen with a minimal daily dose of about one gram,
the blood levels of
PAI-1 and the patients symptomatic relief analysis can be used to determine
whether a larger
dose is indicated. Based upon the data presented below, the projected daily
dose for both human
and veterinary use will be from about 5 to about 200 milligrams/kilogram per
day, and more
usually, from about 10 to about 50 milligrams/kilogram per day.
[0096] The ability of the compounds of this invention to speed muscle recovery
can be
examined in various animal models. One model useful for the demonstration of
activity is the
mouse model disclosed in Am. J. Physiol Cell Physiol. 289: C217-C223, 2005,
herein
incorporated by reference in its entirety. Briefly, in this model, C57BL/6
(wild-type) mice are
anesthethized and the preinjury in situ maximal isometric force of the EDL
muscle measured
(Am. J. Physiol. Cell Physiol. 286: C713-C722, 2004, herein incorporated by
reference in its
entirety). Cardiotoxin (Calbiochem, San Diego Califomia) is injected into the
EDLin three
locations. Subsequent to the injections, the skin is closed and the procedure
repeated in the
contralateral muscle. After recovery, the mice are subjected to the muscle
force evaluation at
predetermined intervals. One group of animals serve as the control group and
one group of
animals is treated with a compound as described in this invention. The
compound can be dosed
orally, IP or subcutaneously as desired. Multiple treated groups can be used
in order to assess
dose response relationships if desired. Exemplary compounds of the methods
described herein
demonstrate the ability to speed a return to normal muscle force pre-injury
versus those in the
control group. Additional evidence for the compounds' salutary effects can be
ascertained by,
for example, morphological examination of the damaged muscle tissue including
staining of
cryosections from treated and control animals and comparing damaged to
undamaged area.
[0097] Compounds of this invention can also be evaluated in mdx mice (see, for
example, Ann Neuro12002;52:832-836, herein incorporated by reference in its
entirety). Briefly,
mdx mice mouse contains a nonsense mutation in the gene for dystrophin
resulting in the
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absence of the protein from the muscle fiber necrosis and the sarcolemma.
Groups of mdx mice
representing a control group and groups of animals treated with compounds of
this invention are
compared over a predetermined time period. In particular, at predetermined
time periods,
animals muscle weights and grip strength are compared (see again Ann
Neuro12002;52:832-
836). After sacrificing of animals at predetermined time points, muscle
weight, muscle fiber
diameter, muscle histopathology measurements can be taken and hydroxyproline
content of the
animals diaphragms can be measured and compared between the treated and
control groups-
Preferred compounds useful for the methods of this invention are those that
positively affect one
or more of the muscle and/or strength parameters.
[0098] Exemplary compounds of formula (I) provided herein can be prepared by
the
methods disclosed in US2003/0125371 which is herein incorporated by reference
in its entirety.
The general schemes (1 and 2) are detailed below:
Scheme 1 Preparation of exemplary compounds of formula (I) for use in the
methods of this
invention
R3 R3 R.
Br Br r\ ~ R nBuLi B(OiPr),. THF (I.1O)_B ~ ~-R-
N ~FlT~orTRF~ N H C I, H_O "
(II) H (III) R, QV) R~
R;
R,71_ RS Rs
(OH) Rr~~B(OH): R ar
Pd, Base `
P d, Base P d, Bese
R; R3 Rs R3
R' rX ~ R X Base R
R_% I N! DMF~ R`% ~ R=
H
R,
(VI)
(V)
C I)_
(COCI)~ \H.~O
ROH O OR O OH
R;. Ra R; Ra
R; r~- .~ O Ra ~r~ . O
I R Base I R_
R; ~ N ACid R? ~ ~ N
R, Ri
(YI I ) ( I)
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[0099] Exemplary compounds of the present invention can be readily prepared
according to the methods of scheme I or 2 using readily available starting
materials, reagents and
conventional synthetic procedures. It is also possible to make use of variants
of these process
steps, which in themselves are known to and well within the preparatory skill
of the medicinal
chemist. In the reaction schemes outlined above, Ri, R2, R3, R4 and R5 are
selected from the
groups as defined previously, or groups readily convertible thereto.
101001 The bromo-indoles (II) were either commercially available or were
prepared
following known literature procedures (Ayer et.al, Tetrahedron Letters, 48
(14) 2919-2924,
1992; Rapoport et.al, JOC, 51, 5106-5110, 1986, herein incorporated by
reference in its
entirety).
[0101] In the method of Scheme 1, the bromo-indoles (II) can be reacted with
alkyl
halides or aryl-alkyl halides using a base such as sodium hydride in DMF or
THF giving the N-
substituted bromo-indoles (III). The N-substituted bromo-indoles (III) can be
converted to the
corresponding boronic acids (N) by treating III in THF with nBuLi, followed by
triisopropyl-
borate and subsequent quenching with aqueous acid. Boronic acids (IV) can then
be subjected to
palladium catalyzed cross-coupling with various substituted aryl-halides
affording the aryl-
indoles (VI). Alternatively, N-substituted bromo-indoles (III) can be
subjected to the palladium
catalyzed cross-coupling with various substituted aryl-boronic acids to afford
the aryl-indoles
(VI). Furthermore, reaction of bromo-indoles (II) with various substituted
aryl-boronic acids
under the palladium catalyzed cross-coupling conditions can afford the aryl-
indoles (V).
Alkylation of (V) with alkyl-halides or aryl-alkyl-halides under basic
conditions as described
above can afford the N-substituted aryl-indoles (VI). Reaction of (VI) with
oxalyl chloride in
methylene chloride followed by quenching with water can afford the desired
ketoacids (I), which
can be purified by crystallization. Alternatively (VI) can be reacted with
oxalyl chloride in
methylene chloride followed by quenching with alcohol to afford the keto-
esters (VII). The
ketoesters (VII) can be purified by either crystallization or chromatography.
Conversion of the
ketoesters (VII) to the corresponding ketoacids (I) can be accomplished by
saponification of the
ester followed by neutralization with an acid such as hydrochloric acid.
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Scheme 2 Preparation of compounds of formula (I) for use in the methods of
this invention
R4 0 0
R3 R5~t~B(OF% R4 R3
R CI
RB r
5\~- C:I- Br r ~R2 Re~ ~Rz
N Pd PPh NaH THF
H ( 3)a H ,
(~~l NaZCO3 (u)
R`R4 R3 R5 R4
Re'' 1 Ri-OH Rs
Re
KOt-Bu, Tol
2
(MlD ~`~ o e Ml ~ R2
0 R,
R5 R4 O
R O
Re'' / ~~ \
1. (COCI)2, THF, r.t. OH
-1
2. H20, Na2CO3 N R2
(l) Rt
[0102] In the method of Scheme 2, an indole (11), substituted on the benzene
ring with
bromide, iodine, or triflate, is coupled with an aryl boronic acid in the
presence of a palladium
catalyst, such as Pd(PPh3)4, a base, such as Na2CO3 or NaHCO3, in a solvent,
such as water,
methanol or ethanol, or in a mixed co-solvent system comprising two or more of
the aforesaid
solvents, at 50-110 C. Boronic acid derivatives of benzene, furan, thiophene,
benz[b]thiophene
and naphthalene are described in the literature and many are presently
commercially available.
The resulting aryl indole (V) can be sulfonylated on nitrogen using
phenylsulfonyi chloride or
toluenesulfonyl chloride in the presence of a base, such as NaH or KOt-Bu, in
an inert solvent,
such as THF or DMF. The resulting 5-aryl-Ihi-arylsulfonyl indole (VIII) is
reacted with alcohols
in the presence of base, such as NaH or KOt-Bu, in an inert solvent,
preferably toluene or DMF,
at 80-200 C, to give 5-aryl-lH-alkyl indoles (VI). Reaction with oxalyl
chloride, neat or in an
inert solvent, affords the indol-3-yl glyoxylic chloride. Quenching the
reaction with water affords
the desired 5-aryl-lH-alkyl indol-3-yl glyoxylic acids (I).
SELECTED PREPARATIONS
[0103] Exemplary compounds of formula (I) provided herein can be prepared by
the
methods disclosed in US Patent No. 7,074,817, which is herein incorporated by
reference in its
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entirety. Seven of the examples from that disclosure are enclosed herein for
illustrative
procedures.
EXAMPLE 1
{1-Methyl-6-[4-(trifluoromethoxy)phenyl]-IH-indol-3-yl}(oxo)acetic acid
Step 1
6-(4-Tritluoromethoxyphenyl)-1 H-indole
[01041 The mixture of 6-bromo-IH-indole (1.22g, 6.22 mmol), 4-
trifluoromethoxyphenyl boronic acid (1.41g, 6.84 mmol),
tetrakis(triphenylphosphine)palladium
(0.213g, 0.184 mmol) and sodium carbonate (2.64g, 24.9 mmoles) in water (12.5
mL), ethanol (4
mL), and toluene (25 mL) was heated at reflux for 1.5 hours then cooled to
room temperature.
The mixture was then evaporated to dryness and the residue was partitioned in
methylene
chloride and water. The organic phase was washed with water, brine, dried over
anhydrous
magnesium sulfate and evaporated to dryness. The residue was purified by flash
chromatography
using 10-30% chloroform in hexane as an eluant. The title compound was
obtained as a white
solid (0.874g, 51%), mp: 165-166 oC. 'HNMR (300 MHz, DMSO-d6): 511.25 (s, 1H)
7.8 (d,
2H, J=7.0 Hz), 7.65 (d, 2H, J=7.0 Hz), 7.4-7.5 (m, 3H), 7.3 (d, IH, J=8.8 Hz),
and 6.45 ppm (s,
1 H).
Step 2
6-(4-Tritluoromethoxyphenyl)-1-methyl-1 H-indole
[0105] To a solution of 6-(4-trifluoromethoxyphenyl)-IH-indole (0.853, 3.08
mmoles)
in dry THF (10 mL) was added sodium hydride (60% dispersion on mineral oil,
0.47g, 12.3
mmol), portionwise. The reaction mixture was stirred under nitrogen for 30
minutes and, then
cooled in ice bath. A solution of iodomethane (0.38mL, 6.1 mmole) in dry THF
(10 mL) was
added and the reaction mixture was stirred for 1 hour at room temperature. The
mixture was
then poured into excess water, acidified with 2N hydrochloric acid and
extracted with ethyl
acetate. The organic phase was washed with brine, dried over anhydrous
magnesium sulfate and
evaporated to dryness. The residue was purified by flash chromatography
(Biotage apparatus)
using 0.5% t-butyl methyl ether in hexane as an eluant. The title compound was
obtained as a
cream-colored solid that was vacuum dried at 66 C (0.623 g, 70%). 'HNMR (300
MHz,
DMSO-d6): 57.85 (d, 2H, J 8.3 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.3 Hz), 7.45
(d, 2H, J=8.3
Hz), 7.3-7.4 (m, 2H), 6.45 (s, 1H), and 3.85 ppm (s, 3H).
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Step 3
Methyl2-[6-(4-trifluoromethoxyphenyl)-1-methyl-I H-indol-3-yl]-2-oxoacetate
[0106] To a solution of 6-(4-trifluoromethoxyphenyl)-1-methyl-lH-indole
(0.304g,
1.04 mmol) in dry THF (5 mL) under nitrogen at 0 C was added oxalyl chloride
(0.11 ml, 1.2
mmol). The reaction mixture was stirred at room temperature for 2 hour. The
mixture was
cooled in an ice bath. Methanol (1 mL) was added. The reaction mixture was
stirred at room
temperature for 1 hour then poured into excess sodium bicarbonate solution and
extracted with
ethyl acetate. The organic phase was washed with water and brine, dried over
anhydrous
magnesium sulfate, and evaporated to dryness. The residue was purified by
flash
chromatography (Biotage apparatus) using 20-50% ethyl acetate in hexane as an
eluant. The title
compound was obtained as a cream-colored solid (0.196g, 50%), mp: 152-153 C.
Mass
spectrum (+APCI, [M+H]+) m/z 378; 1HNMR (400 MHz, DMSO-d6): 58.55 (s, IH), 8.2
(d, 1H,
J=8.3 Hz), 7.95 (t, IH, J=0.77 Hz), 7.90-7.95 (m, 2H,), 7.65 (dd, 1H, J=8.3 Hz
and 1.5 Hz), 7.45
(d, 2H, J-8.6 Hz), 4.0 (s, 3H), and 3.9 ppm (m, 3H).
Elemental Analysis for Ci9H14F3N04:
Calculated: C, 60.48; H, 3.74; N, 3.71.
Found: C, 60.60; H, 3.86; N, 3.60.
Step 4
{1-Methyl-6-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid
[0107] The mixture of inethyl2-[6-(4-trifluoromethoxyphenyl)-1-methyl-lH-indol-
3-
yl]-2-oxoacetate (0.120g, 0.318 mmol), and sodium hydroxide (IN, 1mL, 1.0
mmol) in methanol
(10 mL), was stirred at room temperature for 2.5 hours. The mixture was poured
into excess
water and acidified with 1N hydrochloric acid. The mixture was extracted with
ethyl acetate.
The organic phase was washed with water, brine and dried over anhydrous
magnesium sulfate.
The organic phase was evaporated to dryness and dried under vacuum at 55 C
for 12 hours to
yield the title compound as a yellow solid (0.0686g, 59.1%), mp: 233-235 C
(dec). Mass
spectrum (+APCI, [M+H]+) m/z 364; 'HNMR (400 MHz, DMSO-d6): 513.8-14.0 (br s,
1H), 8.55
(s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (d, 1H, J=1.1 Hz), 7.85-7.95 (m, 2H),
7.65 (dd, 1H, J=8.2
and 1.6 Hz), 7.45 (dd, 2H, J=8.8 Hz and 0.88 Hz), and 4.0 ppm (s, 3H).
Elemental Analysis for C19H14F3NO4:
Calculated: C, 59.51; H, 3.33; N, 3.86.
Found: C, 59.39; H, 3.38; N, 3.71.
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EXAMPLE 2
{1-Benzyl-6-(4-(trifluoromethoxy)phenyl)-1H-indol-3-yl}(oxo)acetic acid
Step 1
1-Benzyl-6-b romo-l H-indole
[01081 A solution of 6-bromoindole (5.0 g, 26 mmol) in dry DMF (45 mL) was
cooled
in an ice bath. Sodium hydride (2.2g of 60% dispersion in oil, 55 nunol) was
added. After
stirring for 30 minutes under nitrogen at room temperature, the reaction
mixture was cooled in an
ice bath, and benzyl bromide (6.1 mL, 51 mmol) was added. After stirring for
one hour at room
temperature, the reaction mixture was poured into excess water, acidified with
2N hydrochloric
acid and extracted with ethyl acetate. The organic phase was then washed with
water and brine,
then dried over anhydrous magnesium sulfate and evaporated to dryness.
Purification of the
residue by flash chromatography using hexane as an eluant and drying for 30
minutes at 60 C
yielded l-benzyl-6-bromo-lH-indole (5.83g, 80%) as a waxy solid, mp: 85-88 C.
Mass
spectrum (+ESI, [M+H]+) m/z 286; 'HNMR (500 MHz, DMSO-d6): 57.7 (d, IH, J=0.61
Hz),
7.50-7.55 (m, 2H), 7.30 (t, 2H, J=7.3 Hz), 7.2-7.25 (m, IH), 7.2 (d, 2H, J=8.4
Hz), 7.15 (dd, IH,
J=8.4 Hz and 1.7 Hz), 6.5 (dd, 1H,-J=3.1 Hz and 0.77 Hz), and 5.45 ppm (s,
2H).
Step 2
1-Benzyl-6-(4-trifluoromethoxylphenyl)-1H-indole
[01091 The mixture of 1-benzyl-6-bromo-IH-indole (0.272g, 0.950 mmol), 4-
trifuoromethoxybenzeneboronic acid (0.217 g, 1.05 mmol),
tetrakis(triphenylphosphine)
palladium (0.0340 g, 0.0294 mmol) and sodium carbonate (0.405g, 3.82 mmol) in
water (1.9
niL), ethanol (1 mL.) and toluene (5 mL) was heated at reflux for 5 hours. The
mixture was
cooled to room temperature and evaporated to dryness. The residue was
partitioned in
methylene chloride and water. The organic phase was washed with brine, dried
over anhydrous
magnesium sulfate and evaporated to dryness. The residue was purified by flash
chromatography using hexane as an eluant affording the title compound as thick
yellow oil.
'HNMR (200 MHz, DMSO-d6): 87.8 (d, 3H, 3=7.7 Hz), 7.65 (d, 2H, J=7.7 Hz), 7.55
(d, 2H,
J=2.0 Hz), 7.2-7.5 (m, 5H), 6.55 (d, 1H, J=1.5 Hz), and 5.5 ppm (s, 2H).
Step 3
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Ethy12-[ 1-benzyl-6-(4-trifluorometh oxylphenyl)-1H-indol-3-yl]-2-oxoacetate
[01101 Following the procedure described in Step 3 of Example 1, ethyl2-[1-
benzyl-6-
(4-trifluoromethoxyphenyl)-1H-indol-3-yl]-2-oxoacetate was prepared from 1-
benzyl-6-(4-
trifluoromethoxyphenyi)-1H-indole (1.20 g, 3.27 mmol), oxalyl chloride (0.85
mL, 10 mmol) in
THF (20 mL), and ethanol (5 mL). Purification by flash chromatography (Biotage
apparatus)
using 5-10% ethyl acetate in hexane as an eluant yielded the title compound as
a yellow gum
(0.128g, 84%). 'HNMR (300 MHz, DMSO-d6): 58.7 (s, 1H), 8.25 (d, 1H, J=7.7 Hz),
8.0 (s,1H),
7.8 (d, 2H, J= 7.7 Hz), 7.65 (dd, IH, J=7.7 Hz and 0.77 Hz), 7.45 (d, 2H,
J=7.7 Hz), 7.25-7.4 (m,
5H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.2 Hz), and 1.35 ppm (t, 3H, J=7.2 Hz).
Step 4
{1-Benzyl-6-[4-(trifluoromethoxy)phenyl]-1 H-indol-3-yl}(oxo)acetic acid
101111 A mixture of ethyl 2-[1-benzyl-6-(4-trifluoromethoxyphenyl)-1H-indol-3-
yl]-2-
oxoacetate (1.27g, 2.72 mmol), potassium hydroxide (0.539 g, 9.61 nunol) in
THF (12 mL) and
water (12 mL) was stirred at room temperature for 3.5 hours. The mixture was
poured into
excess water, acidified with 2N hydrochloric acid, and extracted with ethyl
acetate. The organic
phase was washed with water and brine, dried over anhydrous magnesium sulfate,
and
evaporated to dryness. The residue was dried under vacuum at 92 C for 15
hours to yield the
title compound (0.985 g, 82%) as a yellow solid. A sample crystallized from
isopropanol gave a
solid, mp: 202-204 C (dec.). Mass spectrum (+APCI, [M+HI+) m/z 440; 'HNMR
(400 MHz,
DMSO-d6): 513.8-14.2 (br s, IH), 8.7 (s, 1H), 8.25 (d, IH, J= 8.3 Hz), 7.95
(t, 1H, J=0.73 Hz),
7.8-7.85 (m, 2H), 7.65 (dd, 1H, J= 8.3 Hz and 1.5 Hz), 7.45 (d, 2H, J=8.8 Hz),
7.25-7.4 (m, 5H),
and 5.65 ppm (s, 2H).
Elemental Analysis for C24H16F3NO4:
Calculated: C, 65. 61; H, 3.67; N, 3.19.
Found: C, 65.59; H, 3.54; N, 3.18.
EXAMPLE 3
[5-(4-Acetylphenyl)-1-benzyl-lH-indol-3-yl](oxo)acetic acid
Step 1
1-[4-(1-Benzyi-lH-indol-5-yl)phenyl]-1-eth anone
[0112] A mixture of 1-benzyl-5-bromo-IH-indole (1.00 g, 3.49 mmol), 4-
acetylphenylboronic acid (0.692 g, 4.22 mmol), [1,1'-
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WO 2007/098278 PCT/US2007/005069
bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with
dichloromethane (1:1)
(0.0581g, 0.0711 mmol), potassium carbonate (0.725 g, 5.25 mmol) in dioxane
(35 mL) and
water (3.5 mL) was heated at 65-70 C for 3 hours. The reaction mixture was
evaporated to
dryness and partitioned in ethyl acetate and 2N hydrochloric acid. The organic
phase was
washed with water and brine, dried over anhydrous magnesium sulfate and
evaporated to
dryness. The residue was purified by flash chromatography using (1-10% ethyl
acetate in
hexane and 10-15% chloroform in hexane) to yield 1-[4-(1-benzyl-lH-indol-
5.y1)phenyl]-1-
ethanone as a buff-colored solid (0.262 g, 23%), mp: 134-135 C. 1HNMR (300
MHz, DMSO-
d6): 87.95-8.1 (m, 3H), 7.85 (d, 2H, J=7.7 Hz), 7.5-7.65 (m, 3H), 7.2-7.4 (m,
5H), 6.6 (d, IH,
J=2.5 Hz), 5.5 (s, 2H), and 2.6 ppm (s, 3H).
Step 2
Ethyl 2-[5-(4-acetylphenyl)-1-benzyl-lH-indol-3-yl]-2-oxoacetate
101131 Ethy12-[5-(4-acetylphenyl)-1-benzyl-lH-indol-3-yl]-2-oxoacetate was
prepared
from 1-[4-(I-benzyl-lH-indol-5-yl)phenyl]-1-ethanone (0.255 g, 0.784 mmol),
oxalyl chloride
(0.14 mL, 1.6 mmol), and ethanol (2 mL), following the procedure described in
Step 3 of
Example 1. Purification by flash chromatography using 30-50% chloroform in
hexane as an
eluant and drying at 55 C yielded a brownish solid (0.243g, 73%). 'HNMR (300
MHz, DMSO-
d6): 88.75 (s, 1H), 8.5 (s, IH), 8.05 (d, 2H, J-9.2 Hz), 7.8 (d, 2H, J=7.7
Hz), 7.7 (q, 2H,.*'--8.5
Hz), 7.25-7.4 (m, 5H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.2 Hz), 2.6 (s, 3H), and
1.35 ppm (t, 3H,
J=7.3 Hz).
Step 3
[5-(4-Acetylphenyl)-1-benzyl-lH-indol-3-yl](oxo)acetic acid
[0114] [5-(4-Acetylphenyl)-1-benzyl-lH-indol-3-yl](oxo)acetic acid was
prepared from
ethyl [5-(4-acetylphenyl)-1-benzyl-lH-indol-3-yl](oxo)acetate (0.225 g, 0.529
mmol), and
potassium hydroxide (0.104 g, 1.85 mmol) in THF (7 mL) and water (7 mL)
according to the
procedure described in Step 4 of Example 2. After drying for 15 hours at 96
C, the title
compound was obtained as a tan solid (0.166 g, 79%), mp: 213-214 C (dec.).
Mass spectrum (-
APCI, [M-H]-) m/z 396; 'HNMR (400 MHz, DMSO-d6): 58.75 (s, 1H), 8.5 (d, 1H,
J=1.7 Hz),
8.05 (d, 2H, J=8.3 Hz), 7.8 (d, 2H, J=8.3 Hz), 7.7 (d, 1H, J=8.8 Hz), 7.65
(dd, IH, J=8.7 Hz and
1.6 Hz), 7.25-7.4 (m, 5H), 5.65 (s, 2H), and 2.6 ppm (s, 3H).
Elemental Analysis for C25H19NO4 = 0.50 H20:
Calculated: C, 73.87; H, 4.96; N, 3.45.
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Found: C, 73.54; H, 4.64; N, 3.32.
EXAMPLE 4
{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid
Step 1
1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole
101151 1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole was prepared by
coupling
of 1-benzyl-5-bromo-lH-indole (5.2 g, 18 mmol) and 4-
trifluoromethoxyphenylboronic acid (4.7
g, 23 mmol), using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
(II) complex with
dichloromethane (1:1) (0.88 g, 1. 1 mmol), and potassium carbonate (3.8 g, 27
mmol) in dioxane
(135 mL) and water (13.5 mL) the reaction according to the procedure outlined
in Step I of
Example 3. Purification by flash chromatography (Biotage apparatus) using
hexane as an eluant
yielded the title compound as a light yellow solid (2.8 g, 42%), mp: 62-63 T.
'HNMR (300
MHz, DMSO-d6): 57.85 (s, 1H), 7.75 (d, 2H, J=7.7 Hz), 7.5-7.6 (m, 2H), 7.4 (d,
3H,.t=7.7 Hz),
7.2-7.35 (rn, 5H), 6.6 (d, 1H, J=3.9 Hz), and 5.45 ppm (s, 2H).
Step 2
Ethyl 2-{ 1-benzyl-5-[4-(tritluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetate
101161 Ethyl { 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1 H-indol-3-yl}
(oxo)acetate
was prepared from 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole (2.80 g,
7.62 mmol),
oxalyl chloride (2.0 mL, 23 mmol), and ethanol (4.5 mL) according to the
procedure described in
Step 3 of Example 1. Purification by flash chromatography using 5-10% ethyl
acetate in hexane
as an eluant then drying at 60 C furnished the title compound as a yellow gum
(3.05g, 86%).
'HNMR (300 MHz, DMSO-d6): ~8.75 (s, IH), 8.45 (s, 1H), 7.8 (d, 2H, J=9.2 Hz),
7.75 (d, 1H,
J=9.2 Hz), 7.6 (d, 1H, J=9.2 Hz), 7.45 (d, 2H, J=9.2 Hz), 7.3-7.4 (m, 5H),
5.85 (s, 2H), 4.35 (q,
2H, J=7.5 Hz), and 1.35 ppm (t, 3H, J=7.5 Hz).
Step 3
{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1 H-indol-3-yl}(oxo)acetic acid
(01171 {1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-IH-indol-3-yl}(oxo)acetic acid
was
prepared from ethyl 2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-
2-oxoacetate
(0.463 g, 0.991 mmol), potassium hydroxide (0.224 g, 3.99 mmol) in THF (5 mL)
and water (5
mL) according to the procedure described in Step 4 of Example 2. The title
compound was
CA 02643731 2008-08-26
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obtained as a light yellow solid (0.314 g, 78%), mp 169-171 C. Mass spectrum
(+APCI,
[M+H]+) m/z 440; 'HNMR (400 MHz, DMSO-d6): 513.8-14.2 (br s, 1H), 8.75 (s,
1H), 8.45 (d,
1H, J=1.5 Hz), 7.75-7.8 (m, 2H), 7.7 (d, IH, J=8.5 Hz), 7.6 (dd, 1H, J=8.7
Hz), 7.45 (d, 2H,
J=8.8 Hz), 7.25-7.35 (m, 5H), and 5.65 ppm (s, 2H).
Elemental Analysis for C24H16F3NO4:
Calculated: C, 65.61; H, 3.67; N, 3.19.
Found: C, 65.59; H, 3.54; N, 3.17.
EXAMPLE 5
[1-(4-Methylbenzyl)-5-phenyl-lH-indol-3-yl)(oxo)acetic acid
Step 1
5-Bromo-l-(4-methylbenzyl)-1 H-indole
[0118] NaH (60%, 2.53 g, 63.1 mmol) was added portionwise to a stirring
solution of
5-bromoindole (8.25 g, 42.1 mmol) in DMF (80 mL) at 0 C under a nitrogen
atmosphere over a
period of 10 min. The mixture was then warmed up to room temperature. After
the reaction
mixture was stirred at room temperature for 1 hour, 4-methylbenzyl bromide
(12.0 g, 63.1 mmol)
was added and the mixture was stirred at room temperature overnight. The
reaction was
quenched with aqueous ammonium chloride and diluted with water. The aqueous
phase was
extracted with ethyl acetate. The organic extract was washed with water and
brine, then dried
over anhydrous magnesium sulfate. This mixture was concentrated to give a
crude oil (14.1 g,
71 %). Crystallization from petroleum ether afforded the title compound as a
white solid, m.p:
56-57 C. Mass spectrum (APCI, [M+H]+) m/z 300. 'HNMR (400 MHz, DMSO-d6):
57.73 (s,
1 H), 7.53 (s, 1 H), 7.40 (d, 1 H, J= 8.9 Hz), 7.18 (d, IH, J= 10.5 Hz), 7.09
(d, 2H, J= 8.2 Hz),
7.07 (d, 2H, J= 8.2 Hz), 6.45 (s, IH), 5.35 (s, 2H), and 2.22 ppm (s, 3H).
Elemental Analysis for C16H14BrN:
Calculated: C, 64.02; H, 4.70; N, 4.67.
Found: C, 63.66; H, 4.59; N, 4.71.
Step 2
1-(4-Methylbenzyl)-5-phenyl-lH-indole
[0119] A mixture of 5-bromo-l-(4-methylbenzyl)-1H-indole (1.0 g, 3.33 mmol),
benzeneboronic acid (0.621 g, 5.0 mmol), potassium carbonate (0.691 g, 5.0
mmol), and [1'1'-
bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with
methylenechloride (1:1)
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(0.816 g, 1.0 mmol) in dioxane -water (10:1, 16.5 mL) was stirred at 70 C for
2 day. The
reaction mixture was diluted with water and extracted with ethyl acetate. The
organic extract
was washed with water and brine, and then concentrated to an oil. The residue
was purified by
flash column chromatography using hexane/ethyl acetate (96 : 4) as an eluant
to give the title
compound as a semi-solid (0.48 g, 49 %). Mass spectrum (+ESI, [M+H]+) m/z 298.
'HNMR
(300 MHz, DMSO-d6): 87.80 (s, I H), 7.63 (d, 2H, J= 8.4 Hz), 7.48. (d, 2H, J=
11.1 Hz), 7.38-
7.45 (m, 3H), 7.11 (m, 4 H), 6.52 (d, 2H, J= 2.8 Hz), 5.38 (s, 2H), and 2.22
ppm (s, 3H).
Elemental Analysis for C22HI9N:
Calculated: C, 88.85; H, 6.44; N, 4.71.
Found: C, 88.65; H, 6.42; N, 4.61.
Step 3
(1-(4-Methylbenzyl)-5-phenyl-1 H-indol-3-yl] (oxo)acetic acid
101201 Oxalyl chloride (0.474 mL, 5.43 mmol) was added dropwise to a stirring
solution of 1-(4-methylbenzyl)-5-phenyl-lH-indole (0.46 g, 1.55 mmol) in THF
(15 mL) at room
temperature over a period of 5 minutes under a nitrogen atmosphere. After the
reaction mixture
was stirred at room temperature for 4 hours, the reaction was quenched
carefully with water.
The aqueous mixture was extracted with ethyl acetate. The extract was washed
with water, and
brine, dried over anhydrous magnesium sulfate, and concentrated to give the
title compound as a
yellow solid (0.41 g, 72%), m.p: 195-196 C. Mass spectrum (ESI, [M+H]-') m/z
370. `IiNMR
(400 MHz, DMSO-d6): 8 13.95 (br s, 1H), 8.68 (s, IH), 8.41 (s, IH), 7.63-7.66
(m, 3 H), 7.56 (d,
IH, J= 10.4 Hz), 7.47 (t, 2H, J= 7.5 Hz), 7.35(t, 1 H, J= 7.3 Hz), 7.22(d, 2H,
J= 8.1 Hz),
7.15(d, 2H, J= 8.0 Hz), 5.56 (s, 2H), and 2.25 ppm (s, 3H).
Elemental Analysis for C24H19NO3 - 0.3 H20:
Calculated: C, 76.91; H, 5.27; N, 3.74.
Found: C, 76.85; H, 5.18; N, 3.61.
EXAMPLE 6
[ 1-(4-tert-Butylbenzyl)-5-(3-methylphenyl)-1 H-indol-3-yl](oxo)acetic acid
Step 1
5-Bromo-l- [4-(tert-butyl)benzyll-1 H-indole
[0121] The title compound was prepared from 4-(tert-butyl)benzyl bromide (180
g, 768
mmol) and 5-bromoindole (152 g, 768 mmol) in substantially the same manner, as
described in
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WO 2007/098278 PCT/US2007/005069
Step 1 of Example 5. The product (257 g, 97%) was obtained as a yellow solid,
mp: 108-109 C.
Mass spectrum (ESI, [M+H]+) m/z 342. IHNMR (400 MHz, DMSO-d6): 6 7.73 (s, IH),
7.55 (s,
1 H), 7.44 (d, 1 H, J= 8.71 Hz), 7.30 (d, 2H, J= 7.96 Hz), 7.19 (d, 1H, J=
8.71 Hz), 7.10 (d, 2H,
J= 7.63 Hz), 6.46 (s, IH), 5.36 (s, 2H), and 1.21 ppm (s, 9H).
Elemental Analysis for C19H2OBrN:
Calculated: C, 66.67; H, 5.89; N, 4.09.
Found: C, 66.78; H, 5.86; N, 4.02.
Step 2
1-[4-(tert-Butyl)benzyl]-5-(3-methylphenyl)-1H-indole
101221 The mixture of 5-bromo-l-(4-tert-butylbenzyl)-1H-indole (67.5 g, 197.2
mmol),
3-methylbenzeneboronic acid (27.6 g, 197.2 mmol), potassium carbonate (27.2 g,
493 mmol),
palladium(II) acetate (0.338 g) and tetrabutylammonium bromide (63.5g, 197.2
mmol) in 10%
dioxane in water (degassed, 1.72 L) was stirred at 70 C. The reaction was
monitored by TLC.
3-Methylbenzeneboronic acid (45.2 g, 394.4 mmol) was added in four portions
every '10 hours,
after which time 5-bromo-l-(4-tert-butylbenzyl)-IH-indole was no longer
detected by TLC. The
reaction was cooled to room temperature and the solvent was decanted. The dark
gum-like oil
was washed with water and extracted with petroleum ether (4 x 2 L). The
combined petroleum
ether extracts were washed with water and filtered. This mixture was
concentrated to a volume
of about 1.5 L and allowed to crystallize. The solid was isolated by
filtration and dried under
vacuum at 60 C for 10 hours. to afford the title compound as a white solid
(50.8 g, 73 %), mp:
94-95 C. Mass spectrum (ESI, [M+H]+) m/z 354. tHNMR (400 MHz, DMSO-d6): 6
7.79 (s,
IH), 7.53-7.51 (m, 2H), 7.45 (s, IH), 7.41 (d, 1 H, J= 7.79 Hz), 7.37 (d, 2H,
J=8.55 Hz), 7.32-
7.28 (m, 3H), 7.14 (d, 2H, J= 8.40 Hz), 7.09 (d, 1 H, J= 8.40 Hz), 6.51 (d, l
H, J= 2.75 Hz),
5.38 (s, 2 H), 2.36 (s, 3H), and 1.21 ppm (s, 9H).
Elemental Analysis for C26H27N:
Calculated: C, 88.34; H, 7.70; N, 3.96.
Found: C, 88.24; H, 7.64; N, 3.92.
Step 3
[1-(4-tert-Butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid
[01231 The title compound was prepared from 1-[4-(tert-butyl)benzyl]-5-(3-
methylphenyl)-1H-indole (44.6 g, 126.2 mmol) and oxalyl chloride (22.0 mL,
252.4 mmol) in
substantially the same manner, as described in Step 3 of Example 5. The
product was obtained
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as a yellow solid (51.4 g, 96 %), mp: 128-129 C. Mass spectrum (ESI, [M-H]-)
m/z 424.
IHNMR (400 MHz, DMSO-d6): S 13.50 (br s, 1H), 8.70 (s, IH), 8.40 (s, IH), 7.69
(d, 1H, J=
8.71 Hz), 7.56 (d, 1 H, J= 8.55 Hz), 7.45-7.42 (m, 2H), 7.37-7.33 (m, 3H),
7.24 (d, 2H, J= 8.40
Hz), 7.16 (d, 1H, J= 7.49 Hz), 5.57 (s, 2H), 2.38 (s, 3H), and 1.22 ppm (s,
9H).
Elemental Analysis for C28HZ7NO3:
Calculated: C, 79.03; H, 6.40; N, 3.29.
Found: C, 78.77; H, 6.29; N, 3.25.
EXAMPLE 7
PAI-1 Inhibitors for the treatment of muscular disorders
101241 The mdx mouse is a genetic model of Duchenne and Becker muscular
dystrophies, providing a model system of muscle degeneration with aberrant
regeneration. In
this model, a nonsense mutation in the dystrophin gene results in the absence
of dystrophin from
the sarcolemma, and subsequent muscle fiber necrosis. Conversely, mice
deficient in
plasminogen activator inhibitor-I have improved skeletal muscle regeneration.
It was
hypothesized that a small molecule PAI-I inhibitor, such as, for example {1-
Benzyl-5-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid could potentially
produce beneficial
effects on the skeletal muscle of mdx mice.
[0125] Female mdx mice were purchased from a commercial vendor, and divided
into 2
groups of equal body weight. {1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-
3-
yl}(oxo)acetic acid was formulated into rodent chow at a concentration of I mg
of drug per 1
gram of food (1 mg/g), and this mixture was formed into food pellets. A
standard, pelleted
rodent chow was used as the control diet. One group of mice received the drug-
containing diet,
while the other group received the control diet ad libitum. Each diet was
coded, and the animal
technicians remained blinded to the composition of the diets throughout the
study.
[0126] Eight mice received either the control or drug-containing diet for 9
months. At
the end of the study, the mice were killed, and muscle and body weights were
measured. There
was no change in body weight between groups (28.1 0.45 g for drug-treated
vs. 28.3 0.69 g
for Control). Treatment with the PAI-1 inhibitor resulted in a greater
gastrocnemius muscle
mass, however, as drug-treated mice exhibited a muscle weight of 141.0 4.1
mg compared to
128.9 5.9 mg for control mice (p=O.l 1, 8.6% difference in group means).
Because muscular
dystrophy is a wasting disease, changes in muscle weight are routinely
expressed per unit of
body weight in preclinical studies. Therefore, the individual weight of each
gastrocnemius
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muscle (mg) was expressed relative to total body weight (g). When expressed in
these units,
drug treatment also resulted in an increased muscle weight compared to muscle
weight of mice
feeding on normal chow. In drug-treated mice, muscle weight per unit of body
weight was 5.02
0.13 mg/g, while in mice on the control diet, this value was 4.56 mg/g 0.20
(p--0.07). Taken
together, these data indicate that treatment with the synthetic PAI-1
inhibitor {1-Benzyl-5-[4-
(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid resulted in an
increased relative ratio
of skeletal muscle weight to body weight in a murine model of muscular
dystrophy.
[0127] Various modifications of the invention, in addition to those described
herein,
will be apparent to those skilled in the art from the foregoing description.
Such modifications are
also intended to fall within the scope of the appended claims. Each reference,
including all
patent, patent applications, and publications, cited in the present
application is incorporated
herein by reference in its entirety.
